I HAVE THE PRIVILEGE OF SERVING
AS THE CHIEF EXECUTIVE OFFICER
OF THE AMERICAN ASSOCIATION FOR
THE ADVANCEMENT OF SCIENCE, OR
AAAS MARTIN AND ROSE WACHTEL
CANCER RESEARCH AWARD AND
LECTURE, AND EXECUTIVE PUBLISHER
OF SCIENCE AND THE SCIENCE
FAMILY OF JOURNALS.
I GET TO WELCOME YOU TO THE 11th
ANNUAL AAAS MARTIN AND ROSE
WACHTEL CANCER RESEARCH AWARD
AND LECTURE.
THIS IS WHERE WE RECOGNIZE EARLY
CAREER RESEARCHERS FOR
OUTSTANDING CONTRIBUTIONS TO THE
FIELD.
TODAY'S AWARD WAS MADE POSSIBLE
BY A BEQUEST BY MARTIN WACHTEL.
HE WISHED TO ESTABLISH AN
ENDOWMENT TO RECOGNIZE A AAAS
WORKER IN SCIENCE.
HE WASN'T A SCIENTIST.
HE PROVIDED ALBINO MICE AND RATS
FOR MEDICAL RESEARCH.
HE WAS A FIRM BELIEVER IN THE
POWER OF SCIENTIFIC RESEARCH TO
BENEFIT HUMANITY AND SOUGHT TO
USE HIS WEALTH TO SUPPORT AND
RECOGNIZE THOSE IN THE MEDICAL
COMMUNITY WHOSE WORK WAS HAVING
THE GREATEST IMPACT.
HE INDICATED HE SELECTED THE
AAAS AS THE PLACE TO ESTABLISH
THIS PRIZE BECAUSE OF ITS LONG
AND DISTINGUISHED HISTORY IN ALL
OF THE SCIENCES.
EARLY RECOGNITION OF
MULTIDISCIPLINARY RESEARCH, THE
FACT THERE IS CONVERGENCE
AMONGST THE SCIENCES AND THEY
LEAD TO EVEN MORE CREATIVE AND
INNOVATIVE SOLUTIONS TO PROPS.
AAAS IS 175 YEARS OLD.
IT WAS FOUNDED IN 1848 BY A
BUNCH OF ENTOMOLOGISTS, MOSTLY
MEN IN PHILADELPHIA.
WHAT IS AMAZING TO ME OVER THAT
TIME IS THERE HAVE BEEN
EVOLUTIONS AND REVOLUTIONS IN
THE SCIENCES THAT HAVE ENABLED
US TO MAKE INCREDIBLE PROGRESS.
SO WHEN I THINK OF THE
CHALLENGES THAT WE FACE TODAY,
YOU KNOW, I THINK THAT THERE'S
DAYS WHEN I'M OPTIMISTIC.
ON MY MOST OPTIMISTIC DAYS I
THINK THAT THE SCIENCES CAN
SERVE AS BRIDGES AND CONNECTORS
AROUND THE WORLD TO CURE
DISEASE, TO FEED THE HUNGRY, TO
PROTECT THE PLANET.
BUT THEN ON MY WORST DAYS I
THINK THAT -- I START TO THINK
THAT WE'RE GOING TO RETREAT TO
OUR CORNERS AND WE'RE GOING TO
DO RESEARCH THAT IS ONLY FOR OUR
TRIBE OR ONLY FOR OUR COUNTRY OR
ONLY FOR DEFENSE.
BOTH OF THOSE FUTURES ARE
POSSIBLE.
BOTH OF THEM ARE POSSIBLE, BUT
NEITHER ONE OF THEM IS
INEVITABLE.
NEITHER ONE IS INEVITABLE.
THE AAAS IS STANDING IN THIS
PLACE WHERE WE ARE TRYING TO
MAKE SURE WE GO FOR A MORE
POSITIVE VERSION OF THAT FUTURE
PART OF THAT IS RECOGNIZING THAT
SCIENCE AND THE CREATIVITY, THE
DISCOVERY AND THE JOYFUL PURSUIT
OF IT, THE PART THAT GETS US ALL
INTO IT IN THE FIRST PLACE CAN
BE MARRIED WITH THE AMAZING
THINGS THAT WE HOPE TO IMPACT IN
PEOPLE'S DAILY LIVES.
WHETHER THAT BE MAKING THEIR
LIVES A LITTLE BETTER THROUGH
TECHNOLOGY, HOPEFULLY NOT SOCIAL
MEDIA, BUT SOMETHING ELSE, OR
WHETHER IT BE CURING DISEASE AND
MAKING LIVES HEALTHIER.
A LOT OF THAT IS DRIVEN BY EARLY
CAREER SCIENTISTS.
EARLY CAREER SCIENTISTS.
IN FACT, IT IS WHAT GIVES ME
HOPE.
WHEN I'M ASKED WHAT IS IT THAT
DRIVES MY OPTIMISM IN THE
SCIENCES IN A TIME OF
MULTIPOLARITY AND PULLING APART
OF THE WORLD?
I SAY WHEN I GO TO ANY CAMPUS,
WHEN I GO TO ANY UNIVERSITY R,
WHEN I GO TO ANY RESEARCH
INSTITUTION AROUND THE WORLD, I
DON'T WANT TO MEET WITH THE
SENIOR LEADERS.
I HAVE GOTTEN TO MEET THEM.
MAN, THEY ARE HARD WORKING.
WHEN I SEE THE CREATIVITY AND
INNOVATION, I SEE IT IN THE
EARLY CAREER SCIENTISTS.
THAT IS WHERE I DERIVE MY HOPE
AND OPTIMISM AND I HOPE YOU ALL
WILL, TOO.
NOW, IN ADDITION TO BEING THIS
MULTIDISCIPLINARY SOCIETY, WE DO
PUBLISH "SCIENCE" AND THE
SCIENCE FAMILY OF JOURNALS, AND
THAT'S IT BY THE WAY.
WE DON'T HAVE A THOUSAND
JOURNALS SITTING BACK THERE WE
THROW THINGS INTO.
WE REALLY BELIEVE THAT IT
MATTERS THAT WE ARE IDENTIFYING
AND CURATING WITH THE COMMENT.
I WANT TO RECOGNIZE THE EDITOR
AND ASSOCIATE EDITORS WHO ARE
HERE FOR OVERSEEING THIS AWARD
AND THE SELECTION PROCESS.
THIS IS NOT EASY.
IT TURNS OUT THERE ARE A LOT OF
WONDERFUL, WONDERFUL EARLY
CAREER SCIENTISTS OUT THERE THAT
COULD HAVE EARNED THIS AWARD.
THAT IS WHY YOU ARE GOING TO SEE
AN EXTRAORDINARY TALK TODAY
BUILT ON AN EXTRAORDINARY ESSAY.
NOW, GIVEN MR. WACHTEL'S HISTORY
OF WORKING WITH NIH RESEARCHERS,
I'M SURE HE WOULD BE
PARTICULARLY PLEASED TO KNOW
THIS IS BEING PRESENTED IN
COLLABORATION WITH THE NATIONAL
CANCER INSTITUTE, THE NCI.
I WANT TO ACKNOWLEDGE JULIA
LAMB, CRYSTAL RIVERA FOR PUTTING
THIS TOGETHER.
AND I WANT TO ACKNOWLEDGE AND
INTRODUCE THE DIRECTOR OF THE
CENTER FOR CANCER RESEARCH DR.
TOM -- TOM HAS BEEN A PARTNER
AND IT IS WONDERFUL TO BE IN THE
SAME ROOM WITH HIM AT THIS TIME.
SO TOM, COME ON UP.
[ APPLAUSE ]
>>THANK YOU.
SO YOU CAN TELL IT IS REALLY
TRUE WHAT WAS JUST SAID.
HE DOESN'T MEET WITH SENIOR
LEADERSHIP BECAUSE WE'VE
ACTUALLY NEVER MET.
SO WELCOME ALL OF YOU TO THIS
YEAR'S WACHTEL AWARD.
AND, OF COURSE, I WANT TO THANK
AAAS AND SCIENCE TRANSLATIONAL
MEDICINE FOR LETTING US BE PART
OF THE WACHTEL AWARD.
THIS HAS BECOME AN ANNUAL EVENT.
FOR SOME REASON WE ALWAYS DO
THIS ON A VERY HOT DAY, AT LEAST
THAT IS HOW I REMEMBER IT.
AND, YOU KNOW, SO THIS IS A
REALLY IMPORTANT AWARD AND
EVENT, ACTUALLY.
SO THE WACHTEL AWARD RECOGNIZES
A TRULY OUTSTANDING EARLY CAREER
INVESTIGATOR AND SO, OF COURSE,
THESE LECTURES, BY DEFINITION,
ARE ALWAYS FANTASTIC.
AND YOU WILL SEE THAT TODAY.
TODAY WILL BE NO EXCEPTION.
BUT I THINK THE AWARD AND THIS
EVENT IS ACTUALLY ALSO REALLY
IMPORTANT TO REALLY HIGHLIGHT
AND RECOGNIZE THE REALLY
IMPORTANT CONTRIBUTIONS THAT
EARLY CAREER INVESTIGATORS MAKE.
I WOULD ARGUE THAT ACTUALLY MANY
FIELDS, IT IS REALLY THE EARLY
INVESTIGATORS WHO DRIVE THE
INNOVATION OF A FIELD, THE
PROGRESS IN A FIELD.
SO THIS IS REALLY IMPORTANT TO
RECOGNIZE THAT.
I ALSO THINK IT IS REALLY
IMPORTANT TO RECOGNIZE THESE
CONTRIBUTIONS RIGHT NOW BECAUSE
I THINK THERE IS A THIRD GENERAL
SENTIMENT THAT A CAREER IN
BIOMEDICAL RESEARCH MIGHT NOT BE
AS ATTRACTIVE AS IT USED TO BE.
AND THAT IS OBVIOUSLY A LITTLE
BIT TROUBLING AND IT IS REALLY A
SHAME.
AND OBVIOUSLY, THERE ARE
CHALLENGES.
THERE ARE CHALLENGES IN
BIOMEDICAL CAREERS.
I THINK WE NEED TO LOOK VERY,
VERY CLOSELY AT, YOU KNOW,
COMPENSATION, PARTICULARLY FOR
TRAINEES.
IT IS OBVIOUSLY STILL VERY, VERY
COMPETITIVE, GRANT FUNDING IS
VERY COMPETITIVE, PAYLINES ARE
LOW.
AND I THINK WE ALSO REALLY NEED
TO MAKE SURE THAT EVERYONE,
REGARDLESS OF THEIR BACKGROUND,
HAS AN EQUAL OPPORTUNITY TO
PROGRESS AND HAVE A SUCCESSFUL
CAREER IN BIOMEDICINE.
AND THESE ARE REAL CHALLENGES
THAT WE'RE FACING AS A
COMMUNITY.
BUT I THINK, YOU KNOW, I THINK
IT WOULD BE A SHAME TO LOSE
TALENT.
I THINK IT WOULD BE A SHAME TO
LOSE A WHOLE GENERATION OF
SCIENTISTS BECAUSE OF THOSE
CHALLENGES.
AND THE REASON WHY I SAY THAT IS
BECAUSE, REALLY, IF YOU LOOK
AROUND, THE OPPORTUNITIES WE
HAVE NOWADAYS IN BIOMEDICAL
RESEARCH ARE JUST AMAZING.
THERE ARE SO MANY EXCITING
OPPORTUNITIES OUT THERE.
I THINK WE AS A COMMUNITY HAVE
ACTUALLY DONE FAIRLY WELL OVER
THE LAST DECADES, I WOULD SAY,
IN IDENTIFYING CELLULAR
MECHANISMS CELLULAR PROCESSES
USED FOR THERAPEUTIC TARGETS.
WE HAVE AMAZING TECHNOLOGIES
AVAILABLE.
AND I ALSO THINK WE ARE GETTING
BETTER AT COLLABORATING ACROSS
DISCIPLINES, WHICH I THINK IS
REALLY, REALLY NEEDED TO
TRANSLATE THE BASIC DISCOVERIES
THAT EVERYONE'S MAKES INTO THE
CLINIC.
SO I THINK THERE ARE REMARKABLE
OPPORTUNITIES OUT THERE.
AND WE REALLY WANT TO CAPITALIZE
ON THOSE.
AND SO WE NEED THE EARLY CAREER
INVESTIGATORS.
AGAIN, AS I SAID, YOU KNOW,
EARLY CAREER INVESTIGATORS
REALLY HAVE MADE MANY OF THESE
OPPORTUNITIES ACTUALLY POSSIBLE
AND HAVE CONTRIBUTED TO THESE.
SO, AND AGAIN, I THINK THAT IS
THE SPIRIT OF THE WACHTEL AWARD,
TO RECOGNIZE THAT AND TO
HIGHLIGHT THOSE CONTRIBUTIONS.
SO REALLY IN THAT SPIRIT, AGAIN,
THANK YOU VERY MUCH AND ON
BEHALF OF THE NCI, I WANT TO
CONGRATULATE HUMSA FOR THE
AWARD, OBVIOUSLY.
I'M NOW GOING TO HAND IT OVER TO
ORLA SMITH AND ORLA IS THE
EDITOR OF "SCIENCE TRANSLATIONAL
MEDICINE."
THANK YOU VERY MUCH.
[ APPLAUSE ]
>>THANKS, TOM, AND GOOD
AFTERNOON TO EVERYONE.
AND THANK YOU FOR JOINING US
TODAY.
THE MISSION OF SCIENCE
TRANSLATIONAL MEDICINE IS TO
PROMOTE HUMAN HEALTH BY
PROVIDING AN INTERDISCIPLINARY
FORUM FOR BIOMEDICAL RESEARCHERS
ACROSS SCIENCE, MEDICINE AND
ENGINEERS.
SCIENCE TRANSLATIONAL MEDICINE
IS FLIGHTED TO BE COORDINATING
THE 11th ANNUAL WACHTEL AWARD ON
BEHALF OF AAAS, RECOGNIZING A
LEADING EARLY CAREER SCIENTIST
IN THE FIELD OF CANCER RESEARCH.
WE ARE DELIGHTED TO BE
PARTNERING WITH TOM AND THE
CENTER FOR CANCER RESEARCH AT
THE NATIONAL CANCER INSTITUTE ON
THIS PRESTIGIOUS AWARD.
I WOULD LIKE TO THANK OUR
DISTINGUISHED JUDGING PANEL,
HEINZ LOVELY, LAUREN BIAS, AND
MARK DORSON.
AND NOW WITHOUT FURTHER ADO, I
WOULD LIKE TO HAND OVER TO
ASSOCIATE EDITOR COURT MALO WHO
IS GOING TO INTRODUCE THIS
YEAR'S PRIZE WINNER.
COURTNEY.
[ APPLAUSE ]
>>ALL RIGHT.
HELLO.
I AM COURTNEY MALO AND IT IS
WITH GREAT PLEASURE I AM ABLE TO
INTRODUCE THE WINNER OF THE 11th
ANNUAL WACHTEL CANCER RESEARCH
AWARD.
THIS YEAR'S WINNER IS DR. HUMSA
VENKATESH, A GROUP LEADER AT
BRIGHAM AND WOMEN'S HOSPITAL AT
HARVARD MEDICAL SCHOOL.
SHE IS RECOGNIZED FOR HER WORK
ON RECIPROCAL INTERACTIONS ON
NERVOUS SYSTEM AND CANCERS HOW
NEURAL ACTIVITY CAN PROMOTE
TUMOR PROGRESSION.
SHE IS HER TO TELL US MORE ABOUT
HER GROUNDBREAKING WORK.
DR. VENKATESH, PLEASE JOIN ME.
[ APPLAUSE ]
>>AS A RECIPIENT OF THE AAAS
WACHTEL PRIZE PLEASE ACCEPT THE
PLAQUE.
IT SAYS AAAS MARTIN AND ROSE
WACHTEL CANCER RESEARCH AWARD
PRESENTED TO HUMSA VENKATESH FOR
OUTSTANDING WORK IN THE FIELD OF
CANCER RESEARCH BY AN EARLY
CAREER INVESTIGATOR.
[ APPLAUSE ]
WE WOULD LIKE TO PRESENT YOU
WITH THIS $25,000 CHECK.
>>THANK YOU VERY MUCH.
>>IN ADDITION HUMSA'S ESSAY
DESCRIBING HER GROUNDBREAKING
WORK ON CANCER NEUROSCIENCE HAS
BEEN PUBLISHED THIS WEEK IN
SCIENCE TRANSLATIONAL MEDICINE.
THERE ARE COPIES OF HER ESSAY
OUTSIDE.
PLEASE TAKE ONE.
TODAY'S WEBINAR IS BEING
RECORDED AND AFTER THE
COMPLETION OF DR. VENKATESH'S
PRESENTATION THERE WILL BE 15
MINUTES AVAILABLE FOR QUESTIONS
AND ANSWERS.
WITHOUT FURTHER ADO, I WILL
INVITE DR. VENKATESH TO PRESENT
HER AWARD LECTURE.
>>ALL RIGHT.
I WOULD JUST LIKE TO START BY
TELLING YOU ALL WHAT A SINCERE
HONOR IT SO TO BE HERE TODAY.
THE AAAS STM AND THE NCI
TOGETHER HAVE CREATED A
WONDERFUL OPPORTUNITY FOR
SPECIFICALLY EARLY INVESTIGATORS
AND HIGHLIGHTING WORK THAT IS
BEING DONE IN THE FIELD I THINK
IS REALLY IMPORTANT FOR EARLY
INVESTIGATORS LIKE ME AS WE GET
THE PLATFORM TO LAUNCH OUR
CAREERS.
I'M THANKFUL AND HONORED TO BE
HERE.
SPECIFICALLY TO MARTIN WACHTEL
AND HIS FAMILY FOR ENDOWING THIS
PRIZE.
I THINK IT IS REALLY SOMETHING
SPECIAL AND UNIQUE.
THERE IS NOT A LOT OF
OPPORTUNITIES FOR EARLY
INVESTIGATORS.
FUNDING PAYLINES IS DIFFICULT.
IT IS NICE TO SEE THE AAAS HOW
EARLY RESEARCHERS CAN
CONTRIBUTE.
I THINK THERE IS LOTS OF
EXCITING THINGS TO COME THERE
THE REALM OF CANCER RESEARCH.
HOPEFULLY MY TALK WILL BE
INSPIRING IN POTENTIAL FUTURE
MODULATIONS AND HOW TO TREAT
THESE DEVASTATING DISEASES.
WITH THAT, I WILL BE TALKING
ABOUT PAST WORK AND THE ONGOING
WORK IN MY LAB, TARGETING
ELECTRICAL TRANSMISSION BETWEEN
NEURONS AND CANCER CELLS.
MY EARLY WORK WAS UH
UNDERSTANDING BRAIN CANCER OR
HIGH GRADE GLIOMAS.
AN EXTREMELY DEVASTATING
DISEASE.
DESPITE REALLY UNDERSTANDING
ABOUT THE MOLECULAR LANDSCAPE OF
THESE TUMORS, WHAT IS PROMINENT
IS IT IS TRANSLATED TO VERY
LIMITED APPLICABILITY IN THE
CLINIC.
THAT TELLS US PERHAPS WE NEED TO
STUDY THIS DISEASE MORE
COMPREHENSIVELY.
WHEN I STARTED MY GRADUATE
TRAINING I WANTED TO THINK ABOUT
THIS WHOLISTICALLY AND HOW WE
MIGHT WANT TO STUDY THIS DISEASE
IN A WAY THAT TOOK INTO ACCOUNT
CELL MECHANIC 234I678S THAT MAY
CONTRIBUTE TO MALIGNANT
TRANSFORMATION BUT EXTRINSIC
FACTORS THAT MAY INSTRUCT TUMOR
GROWTH.
HOLISTICALLY THINKING ABOUT
CANCER AS A DISEASE.
IN BRAIN CANCERS THAT INVOLVES A
NUMBER OF DIFFERENT CELL TYPES,
IMMUNE CELLS, VASCULAR CELLS,
BRAIN CELLS.
WHAT IS OBVIOUS AND LARGELY
UNRECOGNIZED AND LEFT OUT OF THE
UNDERSTANDING OF THE MICROVIMPLT
IS THE NEURONS AND NERVOUS
SYSTEM.
WHAT WE WANTED TO UNDERSTAND IS
HOW DO NERVES AND NEURAL
ACTIVITY CONTRIBUTE TO MALIGNANT
DISEASE PROGRESSION.
THIS IS A PRIMARY PATIENT SAMPLE
TAKEN FROM THE BRAIN.
AND WHAT WE DID WAS CLEAR THIS
TISSUE SAMPLE AND STAIN IT FOR
THESE NERVE FIBERS.
YOU CAN SEE EVEN WITHIN THE CORE
OF THIS TUMOR THERE IS A DENSE
NETWORK OF THESE NERVE FIBERS
AND BUNDLES SUGGESTING THESE
NERVES MAY PLAY A CRITICAL ROLE
IN THE CONTEXT OF THE TUMOR
MICROENVIRONMENT.
I LIKE TO CREATE THIS ANALOGY,
SIMILAR TO THE IDEA OF A CANCER
TRYING TO KILL A TREE OR A WEED.
PERHAPS ONE STRATEGY MIGHT BE TO
PLUCK OFF THESE INDIVIDUAL
LEAVES OF THIS WEED OR TREE, BUT
ANOTHER WAY OF GOING ABOUT THIS
IS TO PULL OUT THOSE ROOTS AND
PREVENT THIS WEED FROM TAKING UP
THE NUTRIENTS FROM THE SOIL.
SIMILARLY, THE MICROENVIRONMENT,
WE CAN THINK ABOUT AS NUTRIENT
DENSE SOIL.
WE STUDIED THE SICKLATORY SYSTEM
AND THE BLOOD VESSELS THAT
PROVIDE NUTRIENTS.
THE IMMUNE SYSTEM HAS BEEN
STUDIED FOR DECADES.
WE HAVE MADE HUGE STRIDES IN
HARNESSES THE IMMUNE SYSTEM.
THE NERVOUS SYSTEM IS THE LAST
STONE UNTURNED HOUT THESE TUMORS
DERIVE CUES FROM THESE NEURONS.
WHETHER OR NOT NEURONAL ACTIVITY
CAN PROMOTE TUMOR GROWTH HAS NOT
BEEN PROBED, BUT IT PLAYING A
ROLE HAS BEEN APPRECIATED.
IN THE 1930s, THIS TUMOR CELLS
ARE CLUSTERING AROUND NEURONAL
CELL BODIES WAS DEFINED.
IT IS A HISTOPATHOLOGICAL
FRAMEWORK.
THIS SUGGESTS THAT PERHAPS IN
ADDITION TO A STRUCTURAL
RELATIONSHIP THERE MAY BE A
FUNCTIONAL RELATIONSHIP BETWEEN
TWO DIFFERENT CELL TYPES.
TO ASK THIS QUESTION, DOES
NEURONAL ACTIVITY PROMOTE TUMOR
GROWTH, THAT VERY BASIC
QUESTION, IS SOMETHING THAT
COULDN'T DIRECTLY BE ADDRESSED
UNTIL A LOT OF NOVEL
TECHNOLOGIES WERE DEVELOPED.
WE USE OPTOGENETICS.
A TOOL THAT ALLOWS PRECISE
CONTROL AND FIRING OF NEURONS
WITHIN A VERY SPECIFIC CIRCUIT.
YOU CAN SEE HERE WHEN WE TURN
THE LIGHT ON AND EXPRESS THESE
BLUE LIGHT SENSITIVES IN A
CIRCUIT, WE CAN ATTACH THIS BLUE
LIGHT ON TO THIS MOUSE AND WE
GET A COMPLEX PHISIOMEMETIC SIR
CAT.
WE CAN QUERY HOW DO THE TUMOR
CELLS RESPOND TO THIS ELEVATED
NEURONAL ACTIVITY.
WHAT WE FIND IS SPECIFICALLY
WITHIN THAT ACTIVE MOTOR CIRCUIT
WE SEE A CLEAR INCREASE IN THE
NUMBER OF PROLIFERATING CELLS,
MEASURED BY KR67 AND EDU,
INCORPORATES INTO NEWLY
SYNTHESIZED DNA.
THIS WAS VERY SPECIFIC TO THE
ACTIVE CIRCUIT.
WHEN WE START LOOKING OUTSIDE OF
THE CIRCUIT, WE NO LONGER SEE
THE INCREASE IN PROLIFERATION.
TO UNDERSTAND MECHANICISTICALLY
WHAT WAS GOING ON, WE DEVELOPED
THIS TOOL WHERE WE TOOK THESE
SLICES OPTOGENETICALLY
STIMULATED THEM AND PLACE THE
MEDIUM ON HIGH GRADE CULTURES IN
VETO.
IN THIS DOSE DEPENDENT WAY WE
SEE INCREASE IN PROLIFERATION OF
OUFR CELLS IN RESPONSE TO
CONDITION MEDIUM.
THAT IS SPECIFICALLY ACTIVITY
DEPENDENT.
WHEN WE ADD THE TOX IS, WE CAN
ABROGATE THIS EFFECT THERE IS A
SECRETED SPONSOR THAT IS
INDUCING THIS INCREASE IN
PROLIFERATION IN OUR TUMOR
CELLS.
NOW WE FOUND THIS WAS TRUE IN
NOT ONLY THIS INITIAL PAID
RATTIC COURT KOL GLEE --
CORTICOGLIOBLASTOMA THAT IS IT
IS A BROAD PHENOMENON.
WE FOUND IT WAS USE TO GEL
ELECTROPHORESIS TO IDENTITY THE
PROTEINS DIFFERENTIALLY
REGULATED AS A RESULT OF THIS
NEURONAL ACTIVITY.
THAT GAVE US A CANDIDATE LIST OF
PROTEINS.
SOME TO BE EXPECTED.
PRIMARILY BDNF, AN ACTIVITY
DEPENDENT SECRETED PROTEIN AND
IMPLICATED IN GLIO PROGRESSION.
NEUROLIGAN3 IS A MOLECULE THAT
TYPICALLY FUNCTIONS AT POST SIN
NAS TO STABILIZE PREAND POST
SYNAPTIC CELL TYPES.
IT HAS NOT KNOWN TO BE A
MITOGEN.
IT WAS A SURPRISING FINDING.
NOT ONLY WAS NLGN3 SUFFICIENT TO
PROMOTE THIS GROWTH, A RECOME BY
NANT VERSION OF THIS PROTEIN WAS
NECESSARY IN ORDER TO SEE THIS
ACTIVITY DEPENDENT PROLIFERATIVE
EFFECT.
WHEN WE CREATED OUR ACTIVE
CONDITION MEDIA USING A THIS N
DISTINT -- TO INVESTIGATE THE
CLINICAL RELEVANCE, WE TURNED TO
THE TCGA DATA BASE AND WE FOUND
LOOKING AT JUST A SINGLE STUDY
WHERE THEY LOOKED AT OVER 500
ADULT GBM PATIENTS THAT THE
LEVEL OF NEUROLIGIN THREE
INVERSELY CORRELATED WITH
SURVIVAL.
WE WANTED TO UNDERSTAND HOW
MIGHT WE POTENTIALLY CLINICALLY
TARGET THIS PROTEIN AND THIS
INTERACTION?
SO TO THAT END WE FOUND AS I
MENTIONED WE IDENTIFIED THIS
PROTEIN BECAUSE WE SAW IT WAS
SECRETED IN OUR CONDITION MEDIA.
IT IS CLEARLY ACTIVITY DEPENDENT
MANNER.
WHEN WE WENT BACK TO LOOK AT THE
PEPTIDES IN OUR CONDITIONED
MEDIA, WE NOTICED THEY HAPPENED
TO BE IN THE EXTRA CELLULAR
REGION AND TRANSMEMBRANE AND
INTRASELL YOU LAR DIDN'T SEEM TO
BE PRESENT IN THAT CONDITION
MEDIUM.
THIS IS LIKELY CLEAVED IN THIS
VERY SPECIFIC AND TARGETED
ACTIVITY DEPENDENT MANNER.
WE SOUGHT TO IDENTIFY THE
MECHANISM OF THAT AK TVTY
DEPENDENT CLEAVAGE OF THIS
PROTEIN.
I WILL SPARE YOU THE DETAILS
HERE, BUT THIS WAS SEVERAL
MONTHS OF MY LIFE USING A
COMBINATION OF GENETIC AND
PHARMACOLOGICAL INHIBITION
TECHNIQUES WE FOUND THAT ATOM
10, A COMMON PROTEASE HIGHLY UP
GRADED IN THE TUMOR
MICROENVIRONMENT WAS RESPONSIBLE
FOR THE SECRETION OF THIS
PROTEIN NEUROLIGIN3.
LUCKILY FOR US, ADAM 10
INHIBITORS HAVE BEEN CREATED IN
OTHER NEURODEGENERATIVE
DISEASES.
THEY WEREN'T ACTIVELY BEING USED
IN THE CLINIC.
WE HYPOTHESIZED IF WE COULD
CONVINCE A PHARMACEUTICAL
COMPANY TO LET US USE THEIR
COMPOUND WE COULD TREAT
XENOGRAFTED MICE TO PREVENT
NEUROLIGIN3 SHEDDING AND LIMIT
TUMOR GROWTH.
THIS ADAM 10 INHIBITOR HAD NO
EFFECT ON THESE GLIOMA CELLS IN
VITRO.
THIS WAS NOT A CELL INTRINSIC
PHENOMENON.
ANYTHING IN VEEFO IS WE WERE
HAVING AN EFFECT REMODELING THE
MICROENVIRONMENT AND
INTRACELLULAR REACTIONS.
IN MULTIPLE MODELS OF FWLEE
OHMA, TREATMENT WITH ADAM 10 HIN
HIB TOR IN GLIOMA BEARING MICE
SHOWED THESE TUMORS ACTUALLY
STARTED -- SHOWED REDUCTION IN
THE AMOUNT OF GROWTH, BOTH,
AGAIN, VIA HISTOLOGICAL ANALYSIS
AND VIA JUST OVERALL
BIOLUMINESCEN TROIM.
THIS IS TREATMENT ONBEING WITH
PAID RATTIC GLIOMA WITH AN ADULT
IS STUDY TO BE LAUNCHED LATER
THIS FALL.
WE ARE EXCITED ABOUT THAT.
TAKEN TOGETHER THESE EARLY
STUDIES PLACED THESE ACTIVE
NEURONS IN THE TUMOR
MICROENVIRONMENT.
PLAYING A KEY ROLE IN PROMOTING
GLIOMA GROWTH THROUGH THIS
SIGNALLING MECHANISM, ACTIVITY
DEPENDENT WAY PROTEINS SUCH AS
NEUROLIGIN3, AND OTHER PROTEINS
ARE ACTING ON THESE TUMOR CELLS
TO PROMOTE GROWTH.
HOWEVER, I REALLY WANTED TO COME
BACK IN THE NEXT PART OF MY
STORY DRAWS UPON THIS REALLY
STARK FINDING THAT I SHOWED YOU
IN THESE NEUROLIGIN3 KNOCKOUT
MODELS.
FOR THOSE OF US WHO WORK IN
CANCER RESEARCH YOU CAN
APPRECIATE THE PRESENCE OR
ABSENCE OF A SINGLE MITOGEN
RARELY HAS SUCH AN EFFECT.
PERHAPS NEUROLIGIN3 SECRETION
AND ACTING AS A MITOGEN MAY
REPRESENT ACTIVITY TO DRIVE
TUMOR GROWTH BUT NOT SUFFICIENT
TO EXPLAIN THE MAGNITUDE OF THIS
EFFECT WE ARE SEEING.
WE WANTED TO DIG DEEPER AND
LOOKING AT THE TRANSCRIPTIONAL
LEVEL WE FOUND EXPOSURE TO EXTRA
CELLULAR NEUROLIGIN3 UPREL
REGULATED SYNAPSE RELATED GENES
IN THE TUMOR THEMSELVES.
NEUROLIGIN3 IS A POST SYNAPTIC
ADHESION PROGRAM.
IT IS -- SYNAPTIC STRUCTURAL
PROTEINS AND A LOT OF
INTERESTING RECEPTORS AND
STRUCTURAL PROTEINS SUGGESTED
THERE MIGHT BE A WAY IN WHICH
THESE TUMOR CELLS ARE DRIVING
DIRECT ELECTRICAL CUES FROM
NEURONS FROM DIRECT SYNAPTIC
NEUROTRANSMISSION.
IN COLLABORATION WITH HARVARD,
WE LOOKED AT BIOPSIES OF PATIENT
SAMPLES, PEDIATRIC AND ADULT IDH
MUTANT.
A SUBSET OF CELLS WITHIN ANY
GIVEN TUMOR DO SEEM TO BE
ENRICHED FOR THESE SAME SYNAPSE
RELATED GENES AND STRUG CHURL
SYNAPTIC PROTEINS.
WHEN PLOTTED AS THIS LINEAGE
HIERARCHY THAT TAKES INTO
ACCOUNT FEEN OTIPPIC CELLULAR
STATES WE FIND SUB POPULATION
CELLS HIGHLY ENRICHED FOR
SYNAPSE CELLS, GENE EXPRESSION
PROGRAMS ARE THE SAME CELLS THAT
MOST CLOSELY LOOK LIKE THESE
CELLS.
WHAT IS INTERESTING ABOUT THIS
IS A LOT OF THESE HIGH GRADE
GLIOMAS ARE THOUGHT TO ARISE
FROM CELLS WHO FALL IN THIS
LINEAGE, BUT VERY IMPORTANTLY,
IN ADDITION TO THE NORMAL NEURON
TO NEURON SYNAPSE WE ARE VERY
FAMILIAR WITH, THE AXON DEBRISO
SYNAPSE IS ONE OF THE ONLY OTHER
SYNAPTIC INTERACTIONS DEFINED IN
THE ADULT BRAIN.
SO WE HYPOTHESIZED COULD IT BE
POSSIBLE THAT THESE MALIGNANT
TUMOR CELLS WERE FORMING DIRECT
SYNAPSES WITH HEALTHY NEURONS IN
THEIR TUMOR MICROENVIRONMENT.
WHEN WE EXAMINED THESE PATIENT
DERIVED XENOGRAFT MODELS WE
FOUND THESE AND LABEL THESE POST
SYNAPTIC CELL AND FOUND THEY
WERE UNAMBIGUOUSLY IDENTIFIED AS
THESE TUMOR CELLS.
YOU CAN SEE THE CLEAR SYNAPTIC
CLEFT AND VESICLES THAT
SUGGESTED THIS WAS A DIRECT SIN
NAPPIC INTERACTION OCCURRING
HERE.
WE NEWS NEURON GLIOMA
CO-CULTURING TO MORE PRECISELY
VISUALIZE AND QUANTITY FIZ THESE
SYNAPSES BASED ON THE MARKERS.
WE SAW A NUMBER OF THE
CO-LOCALIZATIONS IN THE CONTEXT
AND IN THE ABSENCE OF
NEUROLIGIN3, WE ACTUALLY SEE
THERE IS MARKED REDUCTION IN THE
NUMBER OF THESE SYNAPSES.
THAT TELLS US PERHAPS IN
ADDITION TO FUNCTIONING AS A
MITOGEN, PERHAPS NEUROLIGIN3 WAS
REGULATED THE FORMATION OF BONA
FIDE NEURON TO GLIOMA SYNAPSES.
WERE THEY TRULY EK TRO
PHYSIOLOGICAL FUNCTIONAL OR FROM
THE CELLS WHICH THESE DEBRIS
OHMAS EMERGE.
WE USE WHOLESALE PATCH
ELECTROPHYSIOLOGY.
WE GRAFTED THE CELLS INTO THE
HIPPOCAMPUS.
THE BRAIN IS A VERY COMPLICATED
ORGAN.
THE HIPPOCAMPUS IS A FEW PLACE
WHERE THERE IS A WELL MAPPED
CIRCUITRY.
WE COULD STIMULATE THESE AXONS
AND WE KNOW THAT THESE AXONS
SPECIFICALLY SIGNAL SYNAPTIC
INPUT DIRECTLY INTO THE REGION
WHERE WE CAN GRAFT OUR TUMOR
KRELS.
WE GRAFTED THESE IN THE CAI
REGION AND USING WHOLESALE
ELECTROPHYSIOLOGY MEASURE THE
RESPONSES OF THOSE TUMOR CELLS.
WE FOUND, INDEED, IN DIFFERENT
GLIOMA TUMOR TYPES THERE IS A
SUB POPULATION OF TUMOR CELLS
THAT RESPOND TO THESE EXCITED
POST SYNAPTIC IN RESPONSE TO
THIS NEURONAL ACTIVITY.
THIS IS ACTIVITY DEPEND AND CAN
BEING A ROW GAITED WITH THE
TOXIN THAT WLOKS THE ABROGATION
OF THE POTENTIALS.
NOT GOING TOO MUCH INTO THE
WEEDS BUT THE PRESENCE OF THIS
PARA PULSE STIMULATION SUGGESTS
THAT THESE CELLS THAT WAS THIS
WAS DIRECT SYNAPTIC
NEUROTRANSMISSION.
THE ELECTROPHYSIOLOGY SUGGESTED
THEY MAY BE MEDIATED BY AMPER
RESENTTORS.
A CALCIUM RESENT TOR SEEMED TO
BE MEDIATING THESE CURRENTS IN
THE TUMOR CELLS.
THAT IS REALLY IMPORTANT BECAUSE
CALCIUM PERMEABLE RECEPTORS ARE
EXPRESSED IN THE BRAIN IN
PRECURSOR CELLS, BUT TYPICALLY
NOT AS PROMINENT IN THE MA CHUF
HEALTHY ADULT BRAIN THAN IN THE
TUMOR CELLS.
THIS MIGHT BE A WAY TO
SPECIFICALLY TARGET TUMOR CELLS
COMPARED TO OTHER NEURONAL TYPES
IN THE BRAIN.
FRANK WINKLER'S GROUP FOUND THE
EXACT SAME PHENOMENON IN ADULT
THREE OH-- GLIOMAS.
THAT WAS REASSURING.
THE IDEA THAT SOMEONE ELSE
INDEPENDENTLY FOUND THIS WAS
QUITE NICE AND LED TO A
WONDERFUL COLLABORATION BETWEEN
THE TWO LABS.
WE CO-SUBMITTED AND THEY ARE
WONDERFUL COLLEAGUES AND
COLLABORATORS.
WITH THIS DEPOT LARIZATION, WE
WANTED TO SEE IF WE COULD
VISUALIZE THESE CURRENTS.
WHAT WE DID WAS EXPRESS
GENETICALLY ENCODED IN OUR TUMOR
CELL.
WE GRAFTED THOSE IN THE
HIPPOCAMPUS AND SHAPED THE
AXSONS.
IN RESPONSE TO THAT STIMULATION
YOU SEE VERY CLEAR EVOKED
CALCIUM TRANSIENTS IN SUB
POPULATION OF THESE TUMOR CELLS.
ABROGATED WITH THE ADDITION OF
THE TOXnd TELLS US THIS IS AN
ACTIVITY DEPENDENT EFFECT.
OF COURSE, IN THE BRAIN, WE
DON'T NECESSARILY NEED TO
STIMULATE ACTIVITY.
THERE IS A PARTICULARLY ACTIVE
REGION OF A XENOGRAFT.
I WANTED TO PUT THIS UP HERE TO
ILLUSTRATE TO YOU ALL THE THE
GREEN SIGNAL YOU ARE SEEING IS
ION FLEX OCCURRING THROUGHOUT
THESE MALIGNANT TUMOR CELL
NETWORKS.
THESE CANCERS ARE ELECTRICALLY
ACTIVE TISSUES.
THIS IS LIKELY GOING TO BE VERY
IMPORTANT MOVING FORWARD.
AS YOU CAN SEE HERE IN THE
STILLS FROM THIS VIDEO, THESE
CALCIUM TRANSIENTS SEEM TO BE
PROPAGATED THROUGHOUT THESE
INTERCONNECTED TUMOR CELL
NETWORKS.
SO AGAIN, THINKING BACK TO FRANK
WINKLER'S GROUP WHO IDENTIFIED
THESE GAP JUNCTION CONNECTED
TUMOR CELL NETWORKS BETWEEN
VARIOUS MALIGNANT CELLS PERHAPS
THIS GAP JUNCTION WAS
FUNCTIONING TO AMPLIFY THESE
ELECTRIC CURRENTS.
WE SEE A LOT OF SYNCHRONIZED
CELLS, NEIGHBORING CELLS THAT
ARE KIND OF EVOKING THESE
CALCIUM TRANSSENTS IN SYNCHRONY.
IT BLOCKED THE PROPAGATION, BUT
IN ANY GIVEN CELL IT VERY
CLEARLY DIMINISHED THE AMOUNT OF
CURRENT SENSED BY ANY INDIVIDUAL
CELL.
THAT TELLS US THE TUMOR NETWORKS
MAY BE FUNCTIONING TO AMPLIFY
ELECTRICAL CUES SENSED BY THE
TUMOR CELLS IN THE
MICROENVIRONMENT.
NOW TO UNDERSTAND WHAT IS THE
RELEVANCE OF ANY OF THIS DEPOT
LARIZATION TO THESE TUMORS, TO
MALIGNANT NETWORKS I WANTED TO
UNDERSTAND IF THERE IS RELEVANCE
TO DEPOT LARIZATION.
TO THAT END WE BLOCKED THIS
NEUROTRANSMISSION BY EXPRESSING
A DOMINANT NEGATIVE VERSION OF
THESE CONCEPTS, MEDIATES THESE
CONNECTIONS.
YOU CAN SEE HERE THAT WITH THE
EXPRESSION OF THIS DOMINANT
NEGATIVE CONSTRUCT REALLY
CLEARLY STARKLY STAGNATES
GROWTH, SIMILAR TO WHAT WE SAW
IN THE NEUROLIGIN3 KNOCKOUT
MODELS.
IF WE OVEREXPRESS THE WILD TYPE
VERSION OF THIS CONSTRUCT, WE
CAN ACCELERATE GROWTH AND
DECREASE MOUSE SURVIVAL.
THE EXPRESSION OF THE DOMINANT
EXTENDED MOUSE SURVIVAL.
IMPORTANTLY IN THE TUMORS OF THE
MICE THAT DID SUCCUMB TO THEIR
TUMORS WE FOUND THESE TUMORS AT
THE TIME OF LETHALITY WERE
COMPRISED OF CELLS THAT TURNED
OFF THE CONSTRUCT OR DIDN'T
EXPRESS IT TO BEGIN WITH THIS
TELLS US THERE IS PERHAPS
EVOLUTIONARY SELECTION OF CELLS
THAT WERE ABLE TO PARTICIPATE IN
THIS SYNAPTIC NEUROTRANSMISSION.
NOW, SO FAR I HAVE TALKED TO YOU
ABOUT HOW NEURONS CAN INFLUENCE
TUMOR CELL GROWTH, BUT IT HAS
BEEN KNOWN FOR QUITE SOME TIME
FWLEE OHMAS CAN REMODEL
MICROENVIRONMENT AND HAVE A
HEFTY INFLUENCE ON NEURONS
THEMSELVES.
IT HAS BEEN THOUGHT TO BE
THROUGH GLUTAMATE SE CESSION AND
A NUMBER OF DIFFERENT
SYNAPSEGENESIS FACTORS BUT WE
HAVE SEEN THAT IN CLINICAL MO
MODELS OF ADULT GLIOMA.
WE FIND A SIMILAR FINDING IN
PEDIATRIC GLEO BLAST OHMA.
WE WERE INTERESTED IN THIS IF
THIS WAS RELEVANT TO PATIENTS.
TO THAT END WE COLLABORATED WITH
A PHENOMENAL NEUROSURGEON AT
UCSF TO PERFORM INTRAOPERATIVE
IN ADULT GBM PATIENTS PRIOR TO
RESECTION.
WHAT WE FOUND IS THAT EVEN
COMPARED TO HEALTHY APPEARING
TISSUE, THIS TUMOR INFILTRATED
REGIONS OF THE BRAIN EXHIBITED
THIS CLEAR INCREASE IN HIGH
GAMMA BAND POWER WHICH
CORRELATES WITH INCREASED
NEURONAL ACTIVITY.
IT TELLS US THESE GLIOMAS ARE
CAPABLE OF REMODELING THEIR
MICROENVIRONMENT SUCH THEY
INCREASE NEURONAL ACTIVITY AND
CREATE FEEDBACK MECHANISM WHERE
MULTIPLE MECHANISMS ACTIVITY
DEPENDENT GROWTH ARE POE TEN
SHATED.
IT IS AN EXCITING TIME TO START
THINKING ABOUT CLEAR RECIPROCAL
INTERACTIONS BETWEEN NEURONS AND
MALIGNANT TUMOR CELLS.
WHAT IS CLEAR NOW IS ATTACKING
THIS NEW ANGLE OF DISEASE
PROGRESSION IS GOING TO BE
CRUCIAL TO THINKING OF NOVEL
THERAPIES.
MULTIPLE GROUPS ARE THINKING
ABOUT WAYS TO TARGET THESE
INTERACTIONS.
NEURON TO TUMOR SYNAPTIC
INTERACTIONS, NEURONAL
HYPEREXCITABILITY AND WAYS WE
CAN FOCUS ON ACTIVITY MECHANISMS
OF GLIOMA GROWTH.
WE'VE ALREADY FOUND A NUMBER OF
DIFFERENT ALREADY EXISTINGS
NEUROMODULATORY AGENTS -- TO
BEGIN WITH, THAT SEEM TO
STAGNATE FWLEE OHMA GROWTH IN
PRECLINICAL MODELS AND SOME OF
WHICH ARE MOVING INTO CLINICAL
TRIALS, BUT THERE IS A LOT OF
WORK ONGOING IN THE FIELD VERY
BROADLY SPEAKING THAT IS REALLY
THINKING ABOUT THE BROAD
APOLITICABILITY OF THESE
DRUGGINGS ACROSS MODELS AND THE
POSSIBILITY OF REPURPOSING THESE
ALREADY EXISTING CLINICALLY
AVAILABLE AGENTS THAT ARE USED,
ANTI-EPILEPTIC, ANTIDEPRESSANTS
WE COULD REPURPOSE TO TREAT THIS
DISEASE.
WHAT IS CLEAR IS NEURONAL
ACTIVITY DRIVES TUMOR GROWTH.
THROUGH REPAIR MECHANISMS AS
WELL AS POTENTIALLY DIRECT
ELECTRIC RO CHEMICAL SYNAPTIC
NEUROTRANSMISSION.
WE SEE FUNDAMENTAL PROPERTY OF
CANCER IS ELECTRICAL PROPERTY IS
CRITICAL TO OVERALL PROGRESSION.
THIS IS A REALLY EXCITING TIME
TO REFRAME OUR UNDERSTANDING OF
MALIGNANT TISSUE.
PRIMARY BRAIN CANCERS THERE ARE
A NUMBER OF FOLLOW UP QUESTIONS
TO BE ADDRESSED, LOTS OF PEOPLE
REALLY WORKING ON UNDERSTANDING
THESE RESIP ROW CALL
INTERACTIONS BETWEEN THE TWO AND
HOW WE MIGHT TARGET THEM, BUT
MOVING FORWARD WHAT REALLY
PIQUED MY INTEREST AND HAS BEEN
A FOCUS OF MY LAB IS REALLY
UNDERSTANDING HOW NONGLIAL
DERIVED MALIGNANCIES MAY HIJACK
THESE NEURONAL CUES.
OFTENTIMES WHEN I PRESENTED TO
NEUROSCIENTISTS, CANCER
BIOLOGISTS THOUGHT THIS IS
GREAT, ELECTRICAL PROPERTIES.
WHEN I PRESENTED TO
NEUROSCIENTISTS THEY WERE LIKE,
WELL, THESE ARE CELLS THAT
ORIGINATE FROM THE BRAIN.
IT MAKES SENSE THEY ARE
ELECTRICALLY ACTIVE.
WHAT WAS INTERESTING IS THINKING
ABOUT NONGLIAL DERIVED CANCERS,
THAT END UP IN THE BRAIN, CAN
THEY DERIVE THIS NEURONAL INPUT
TO FACILITATE THEIR OWN GROWTH.
AND SO THOUGH I LARGELY FOCUS ON
PRIMARY BRAIN CANCERS, OUR LAB
HAS TURNED TO THINKING ABOUT
METASTISES AS WELL AS ANOTHER
PROJECT WE ARE THINKING ABOUT IN
PRIMARY LUNG CANCER IN REF RAL
NERVE INNOVATION.
TO COME BACK TO METASTICES
OUTNUMBER ALL BRAIN CANCERS 10
FOLD.
THEY ARE THE CRITICAL CAUSE OF
LETHALITY AND WE HAVE SOME DRUGS
THAT ARE EFFECTIVE IN TREATING
EXTRA CRANIAL DISEASE.
WHEN IT GETS TO METASTASES WE
HAVE LIMITED TREATMENT OPTIONS.
SORRY.
I DID WANT TO MENTION THIS IDEA
OF NEURAL ACTIVITY IN THE
CONTEXT OF BRAIN METASTASES HAS
BEEN THOUGHT ABOUT.
BREAST CANCER BRAIN METASTASES
SHOWED THEY SIT NEXT TO THESE
NEURONS TO USURP GLUTAMATE AND
DERIVE THAT GLUTAMATE TO PROMOTE
THEIR OWN GROWTH VIA MDAR
RECEPTOR SIGNALS.
THINKING ABOUT OTHER CANCERS
THAT MAY BENEFIT FROM THIS
NEURONAL INPUT, OUR LAB HAS BEEN
THINKING ABOUT SMALL CELL LUNG
CANCER ACCOUNTS FOR 15% OF ALL
LUNG CANCERS.
THE REASON WE CHOSE TO STUDY
THIS CANCER IS IT HAS AN
EXTREMELY HIGH PROPENSITY TO END
UP IN THE BRAIN AND THESE SMALL
CELL LUNG CANCERS ARE THOUGHT TO
BE DERIVED FROM PULMONARY CELLS
IN THE LUNG.
THEY HAVE A NEURAL PHENOTYPE SO
NEURONS ARE PLAYING A ROLE IN
THIS CONTEXT AS WELL.
WE USED MULTIPLE DIFFERENT
MODELS.
I WILL TELL YOU ABOUT THE
GENETIC MODEL OF SMALL CELL LUNG
CANCER DEVELOPED AT STANFORD, A
CLOSE COLLABORATORS AND PRIMARY
LUNG METASTA SIZES TO THE LIVE
AND SPLEEN.
THERE ARE NO GREAT MODELS FOR
METASTASES TO THE BRAIN.
I WANT TO EMPHASIZE THIS WAS AN
UNDERSTANDING OF HOW NEURONAL
ACTIVITY CAN AFFECT GROWTH ONCE
THE METS A -- METASTASES.
THESE EXPREX OF THESE PROGRAMS
CORRELATES WITH MORE METASTATIC
DISEASE AND LOWER SURVIVAL
RATES.
YOU CAN SEE AT HIGH RESOLUTION
THEY LOOK NEURONAL WITH AXON
PROTRUSIONS THAT ALMOST LIKE
LIKE DENDITIC SPINES.
USING STAINING IN THESE ANIMAL
MODELS AND PRIMARY PATIENT BRAIN
TISSUE WE CAN SEE THERE IS VERY
CLEAR INTERACTIONS BETWEEN
NEURONS LABELED HERE IN WHITE
AND TUMOR CELL PROCESSES
SUGGESTING THAT SIMILAR TO DPLEE
OHMAE -- GLIOMAS THERE MIGHT BEA
FUNCTIONAL RELATIONSHIP.
JUST USING HNE STAINING, WE
THINK OF THESE METS GROWING AT,
WE SEE A LOT OF AREAS WHERE WE
SEE EXTENSIVE NEURONAL
INFILTRATION.
IF WE LOOK AT THE CELLS IN THE
REGION OPPOSED TO 'ONES AWAY
FROM THE NEURONS WE SEE HIGHER
LEVEL OF PROLIFERATION IN THE
CELLS CLOSER TO THE AXON FIBERS.
AND SO THINKING FUNCTIONALLY
ABOUT THE RELEVANCE OF THESE
INTERACTIONS WE DECIDED TO APPLY
PAST TECHNOLOGIES TO UNDERSTAND
HOW THESE NEURONS MAY PLAY A
ROLE IN THE CONTEXT OF SMALL
CELL LUNG CANCER GROWTH.
IN OUR IN VITRO MODELS, WE
ISOLATED THESE CORTICAL NEURONS
FROM MICE AND CULTURED THEM WITH
SMALL CELL LUNG CANCER CELL.
AND WE SEE CLEAR PROLIFERATION.
AN ACTIVITY DEPENDENT EFFECT.
THIS WAS SPEFGLY IN A SMALL CELL
LUNG CANCER TYPE A, A VERY
SPECIFIC SUBTYPE OF LUNG CANCER,
BUT EVEN IN A SEPARATE SUBTYPE
OF SMALL CELL LUNG CANCER WE SEE
A SIMILAR PHENOMENA.
INNOVATION MAY PLAY A ROLE COULD
BE A BROADLY APPLICABLE
PHENOMENON THAT RELATES TO
MULTIPLE CELLULAR STATES WITHIN
SMALL CELL LUNG CANCERS.
REALLY, DESPITE THE FACT THAT WE
KNOW NEURONS MAY PLAY RA ROLE OF
THE TUMOR MICROENVIRONMENT, WE
WANTED TO UNDERSTAND WHAT DID
THAT MEAN IN VEEFO SETTING.
USING THE SAME TOOLS AS THE
GLIOMAS, WE USED A MODEL HERE
THAT ALLOWED FOR BOTH THE
ALAGRAFTING WITH TUMOR CELLS
WITH THIS STIMULATION.
WE FOUND IN RESPONSE TO THIS
ELEVATION OF NEURONAL ACTIVITY
WE SEE INCREASE IN SMALL CELL
LUNG CANCER GROWTH AND
PROLIFERATION.
COMING BACK TO THIS IDEA OF
METASTATIC ABILITY AND INVASION,
WE SEE TUMORS OF THE MICE THAT
ARE STIMULATED LOOK MORE DIFFUSE
THAN CONTROL COUNTERPARTS.
WHEN QUANTIFIED YOU CAN SEE
THERE IS A CLEAR INCREASE IN THE
SPREAD OF THESE TUMORS IN
RESPONSE TO ELEVATED NEURONAL
ACTIVITY, SUGGESTING THERE IS A
FUNCTIONAL IMPACT OF NEURONS IN
INTRACRANIAL SMALL CELL LUNG
CANCER PROGRESSION.
NOW WE HAVE SEEN THIS FUNCTIONAL
RELEVANCE OF ACTIVE NEURONS IN
THE CONTEXT OF THE
MICROENVIRONMENT WE CAME BACK TO
UNDERSTANDING THIS STRUCTURAL
INTEGRATION OF THESE TUMOR CELLS
INTO THE NEURONS AND THE HEALTHY
MICROENVIRONMENT AND WHAT WE SEE
IS WE DO FIND EVIDENCE OF DIRECT
SYNAPTIC INTERACTIONS, I
DESCRIBED TO YOU WITH THE
GLIOMAS.
WE SEE A NUMBER OF CELLS THAT
SIT SIMILARLY AS THE BREAST
CANCER CELLS, PERISYNAPTICALLY.
THERE ARE DIFFERENT CELLULAR SUB
POPULATIONS THAT BEHAVE VERY
DIFFERENTLY.
WHAT IS CLEAR IS THERE IS SOME
CROSSTALK AND SOME INTEGRATION
WITH THESE SMALL CELL LUNG
CANCER CELLS AND NEURONS IN THE
BRAIN AND PERHAPS MIGHT BE A
REASON THEY ARE SO WELL EQUIPPED
TO THRIVE IN THAT BRAIN
MICROENVIRONMENT.
TO UNDERSTAND AGAIN
MECHANICISTICALLY WHAT IS GOING
ON HERE, WE TOOK OUR SMALL CELL
LUNG CANCER CELLS CO-CULTURED
WITH OUR NEURONSES AND SEE
YENSED THEM WITH THE CELLS THAT
WERE CULTURED ALONE.
THEY DO UPREGULATE A NUMBER OF
DIFFERENT I ONCHANNEL RECEPTORS
THAT INCLUDED GLUTAMATERGIC
RECEPTORS AND A UP TAKE OF GABBA
RESENTTORS SO AN ADDITIONAL
NEURAL SET POPULATION COULD BE
INVOLVED.
WE PROBE THE FUNCTIONAL
INTERACTIONS AND DEPOT
LARIZATION THAT IS OSECURING IN
THESE CELLS TO QUERY THE SBE
SBRAGS OF CELLS.
WE COLLABORATED WITH ANOTHER LAB
AND FOUND IN RESPONSE TO
NEURONAL ACTIVITY WE SEE
EVIDENCE OF EVOKED CURRENTS AND
RESPONSE TO THE NEURONAL
STIMULATION BUT WHAT LOOK LIKE
SPONTANEOUS GLUTAMETERGIC IN
MALIGNANT SMALL CELL LUNG CANCER
CELLS.
EXCITEDLY, THIS IS VERY NEW.
THIS SLIDE IS THROWN TOGETHER.
WHAT WE ALSO SEE IS WE HAPPEN TO
SEE A HIGH PROPORTION OF CELLS
THAT EXHIBIT THESE GABBA IN OUR
TUMOR CELLS.
WE THINK ABOUT GLUTAMATE IN THE
NORMAL BRAIN DEPOT LARIZING
TRANSMITTER AND GABBA AS AN
INHIBITORY NEUROTRANSMITTER.
HERE WE WERE SEEING THESE GABBA
CURRENTS SO THINKING HOW THAT
MIGHT MAKE SENSE GABBA IN THIS
CONTEXT WAS DEPOLARIZING LIKE
FLUTE -- GLUTAMATE.
GABBA INDUCED THIS OUTWARD
CURRENT SAYING THAT GABBA WAS
DEPOT -- DEPOLARIZING.
BOTH GLUTAMATE AND GABBA
NEUROTRANSMITTERS WERE ACTING ON
THESE TUMOR CELLS TO INDUCE
DEPOLARIZING EFFECT.
WE SPECIFICALLY ISOLATED
GABBAURGIC NEURONS WERE HAVING A
STRONG PROLIFERATIVE EFFECT ON
THE SMALL CELL LUNG CANCER
CELLS.
WE SPECIFICALLY NOW EXPRESSED
THESE OPSINS IN INTRANEURON
POPULATION AND FOUND THERE WAS A
VERY ROBUST INCREASE IN SMALL
CELL LUNG CANCER GROWTH UPON
ACTIVATION OF INTER NEURONS.
SUB POPULATIONS WERE DRIVING
POPULATIONS IN NONGLIAL TUMORS.
WE WERE ABLE TO SEE NOT ONLY THE
SPONTANEOUS CALCIUM TRANSIENTS
BUT CLEAR ELICITED CALCIUM
TRANSIENTS IN RESPONSE TO
NEURONAL ACTIVITY THAT WERE
DIMINISHED UPON ABROGATION OF
ACTION POTENTIALS.
THIS REALLY FOR THE FIRST TIME
TELLS US DESPITE NOT ORIGINATING
FROM CELLS IN THE BRAIN, SMALL
CELL LUNG CANCER CELLS HAVE
CAPACITY TO INTERPRET IN
NEURONAL INPUT.
TO FUNCTIONALLY UNDERSTAND THE
ROLE OF DEPOLARIZATION, WE
WANTED TO UNDERSTAND HOW MEM
DRAIN DEPOLARIZATION MAY BE
FUNCTIONING.
TO EXPRESS THE OPSINS IN THE
NEURON MICROENVIRONMENT, WE
EXPRESSED THEM IN THE TUMOR
CELLS.
IMPLANTED INTO THE MICE AND
CHRONICALLY DEPOLARIZED IN VEEFO
USING BLUE LIGHT WHERE WE
DIRECTLY DEPOLARIZE THE TUMOR
CELLS AND THAT PROMOTED GROWTH.
MEMBRANE DEPOLARIZATION ON ITS
OWN INDUCES GROWTH SIGNALLING
CASCADE IN THESE TUMOR CELLS AND
ACTIVELY WORKING ON
UNDERSTANDING WHAT THOSE VOLTAGE
PATHWAYS THAT MEDIATE THIS
GROWTH WILL BE.
MORE TO COME ON THAT NEXT TIME.
I ALSO WANTED TO MENTION THAT AS
I MENTIONED THIS WAS A VERY
SPECIFIC SUB POPULATION OF CELLS
THAT WAS INTEGRATED THESE CUES.
THERE WAS A VERY SPECIFIC SUB
POPULATION OF CELLS THAT SHIFTED
MORPHOLOGY.
THEY SEEM TO BE CONNECTED VIA
GAP JUNCTIONS AND THEY
ASSOCIATED ALSO WITH THIS
UPREGULATION OF ASTROCYTIC GENE
STRUCTURE.
THIS SYNAPTIC ASTROCYTIC.
WE KNOW AS ASTROCYTES MAY BE
RECIPROCAL SIMILAR TO WHAT WE
THOUGHT IN THE GLIOMAS.
USING THESE ARRAYS AND WE HAVE
MOVED TO SETTING THIS IN VEEFO
USING FIELD POTENTIAL RECORDINGS
FROM IN VEEFO SLICES WE SEE THE
NEURONS AND THE PRESENCE OF
THESE SMALL CELL LUNG CANCER
CELLS PRESENT HYPEREXSIBLT WITH
INCREASED SPIKED NUMBER AS WELL
AS INCREASED SPIKE AMPLITUDE.
AGAIN, TELLING US THESE
RECIPROCAL INTERACTIONS ARE
IMPORTANT TO TARGET MOVING
FORWARD.
THIS IS ASSOCIATED WITH AN
INCREASE IN THE SYNAPSE NUMBER
IN THE NEURONS SURROUNDING THE
SMALL CELL LUNG CANCER CELLS.
SO IN SUMMARY WHAT WE NOW KNOW
IS WE SEE NEURONAL INFILTRATION
OF SMALL CELL LUNG CANCER IN THE
BRAIN.
THIS NEURONAL ACTIVITY SEEMS TO
PROMOTE INTRACRANIAL CANCER
GROWTH AND INVOKE CANCER
TRANSIENTS IN THE CELLS AND
THESE CELLS CAN PROMOTE
HYPEREXCITABILITY IN THEIR TUMOR
MICROENVIRONMENT.
THERE ARE A LOT OF REMAINING
QUESTIONS WITH THOSE MECHANISMS
THAT MEDIATE THE GROWTH
PROMOTING SIBLING PATHWAYS AFTER
MEMBRANE DEPOLARIZATION.
MIGHT THESE SYNAPTIC PATHWAYS
EXIST.
WE ARE ACTIVELY WORKING ON THESE
QUESTIONS.
I WANT TO TELL YOU A DIFFERENT
STORY THAT FOCUSES ON
UNDERSTANDING THE ROLE OF
PERIPHERAL NERVOUS SYSTEM INN
INNERVATION.
IT IS IMPORTANT IN A NUMBER OF
DIFFERENT ORGANS OUTSIDE OF THE
CONTEXT OF THE BRAIN,
NEUROTROPHIC FACTORS.
ADDITIONAL, IN A NUMBER OF
DIFFERENT CANCERS, BREAST
CANCERS AND SKIN CANCERS AND
GASTRIC CANCERS AND PROSTRATE
CANCERS, INNERVATION HAS PLAYED
A ROLE.
AFTER DEMONSTRATING THAT IT WAS
SO IMPORTANT TO INTRACRANIAL
SMALL CELL LUNG CANCER GROWTH WE
HYPOTHESIZED PERHAPS THIS IDEA
OF INNERVATION IN THE LUNG MIGHT
BE AN IMPORTANT QUESTION TO TRY
TO ADDRESS.
AND SO TO THAT END, WE LOOKED AT
A NUMBER OF PRIMARY PATIENT
SAMPLES FOUND THAT THEY HIGHLY
EXPRESS A NUMBER OF THESE SAME
ION CHANNEL RECEPTORS SYNAPSE
RELATED GENES.
IF WE LOOK AT THE TUMORS
THEMSELVES, THEY SEEM TO BE
CLEARLY INNERVATED WITH SENSORY
NERVE FIBERS IN THE CONTEXT OF
THE LUNG.
AND SO TO UNDERSTAND HOW
IMPORTANT THE ROLE OF INN
INNERVATION WAS, WE CAME BACK TO
SPONTANEOUS SMALL CELL LUNG
CANCER MODEL WHEREBY THEY FORM
AFTER INHALATION OF THIS VIRUS
THEY CLEARLY FORM PRIMARY LUNG
TUMORS, THIS IS VERY CLEAR TUMOR
EVOLUTION.
WE WANTED TO TRACK THESE MICE
OVER TIME TO SEE HOW IT AFFECTED
OVERALL TUMOR GROWTH.
WHAT WE SAW AFTER 10 WEEKS POTE
VAGOTOMY WE SAW CLEAR
DISTINCTION AND DIFFERENCE
BETWEEN THE TUMOR SIZE IN THE
PRIMARY LUNG OF THESE MICE THAT
HAD UNDERGONE VAGOTOMY VERSUS
MICE SHAM MA LIPLAT -- MANIPULA.
WE CAN SEE THERE IS A PRIMARY
EFFECT IN THE PRIMARY TUMOR
BURDEN.
THE SHAM SURGERY WERE ENTIRE PLI
ENCAPSULATED THE TUMORS.
THE SHAM MANIPULATED MICE HAD
LITTLE TUMOR BURDEN IF ANY AT
ALL.
THAT WAS A STARK FINDING.
AND WITH THIS DIMINISHING OF THE
PRIMARY TUMOR BURDEN WHAT IS
VERY CLEAR IS THAT THE
METASTASES TO THE LIVER WAS
COMPLETELY GONE.
YOU CAN SEE HERE IN THE CONTROL
MICE YOU SEE THESE VERY CLEAR
LIVER MICE DISTINCT SIX-MONTH
TIMELINE.
EVERY MICE THAT UNDERWENT
VAGOTOMY WAS CLEAN, NO
METASTASES AND SURVIVAL.
THIS VAGAL INTEGRATION IS
CRITICAL TO SMALL CELL LUNG
CANCER PROGRESSION.
THERE IS A REAL POTENTIAL TO
HARNESS THE POWER OF THE NERVOUS
SYSTEM AND NEURAL INTERACTIONS
IN THE CONTEXT OF NOPT ON-- NOT
ONLY PRIMARY BUT SECONDARY TUMOR
GROWTH.
GOING FORWARD THAT IS NOT ONLY
THE BRAIN, BUT OTHER CANCERS
OUTSIDE OF THE CNS AS WELL.
MOVING FORWARD MY LAB IS
THINKING ABOUT UNDERSTANDING THE
MECHANISMS THAT DRIVE ACTIVITY
MEDIATED GROWTH IN BRAIN
METASTASES AND INTEGRATION AT
THE PRIMARY SITE AND PERIPHERAL
NERVOUS SYSTEM ROLE IN THE
DIRECT ACTION OF THE TUMOR AND
REMODELING THE MICROENVIRONMENT
AS A WHOLE AND HOW THE NERVOUS
SYSTEM MAY IMPACT THE IMMUNE
SYSTEM TO CREATE AND PRIME A
SPECIFIC ORGAN FROM MALIGNANT
OUTGROWTH.
WE HAVE STARTED STUDIES THINKING
ABOUT TUMORS SYSTEMICALLY.
WHAT HAS BEEN VERY CLEAR IS THAT
THINKING ABOUT THIS DISEASE AS A
HOLISTIC PERSPECTIVE AND
BIOLOGICAL SYSTEMS COMMUNICATE
WITH ONE ANOTHER IS VERY
IMPORTANT MOVING FORWARD.
I WILL END BY A PLUG FOR CANCER
NEUROSCIENCE AS A WHOLE.
THIS IS A VERY EXCITING NEW
FIELD.
THIS IS TAKEN FROM A REVIEW WE
JUST WROTE ILLUSTRATING A LOT OF
MECHANISMS THROUGH WHICH THE
NERVOUS SYSTEM HAS THE
CAPABILITY OF MODULATING
MALIGNANT GROWTH, DIRECT
INTERACTIONS I TALKED ABOUT
TODAY, AND SIGNALLING MECHANISMS
BETWEEN NERVES, TUMOR CELLS AND
OTHER CELLS IN THE TUMOR
MICROENVIRONMENT.
THE SYSTEMIC INTERACTIONS TO THE
WHOLE ACCESS OF NEURAL IMMUNE
INTERACTIONS THAT I THINK IS
GOING TO BE HUGE IN THE CONTEXT
OF NEURAL IMMUNOONCOLOGY.
WE CAN SEE THE ROLE THE NERVES
ARE PLAYING IN THIS ENVIRONMENT.
CANCER CELL INTRINSIC
ENVIRONMENT SHOW NEUROBIOLOGICAL
PROPERTIES THAT NEED TO BE
APPRECIATED.
I DIDN'T EVEN GET TO THIS LAST
PANEL THINKING ABOUT HOW CANCER
THERAPY AFFECTS THE NERVOUS
SYSTEM AS A WHOLE.
WE ARE FINDING THESE THERAPIES
CAN HAVE DEBILITATING EFFECTS ON
THE NERVOUS SYSTEM WITH
COGNITIVE DEFICITS AND THAT
PERHAPS MIGHT BE A WAY IN WHICH
THEY ARE INDIRECTLY AFFECTING
TUMOR GROWTH ESSENTIALLY
DEGRADING THE NERVOUS SYSTEM AS
A WHOLE.
LOOKING INTO THOSE MECHANISMS IS
IMPORTANT MOVING FORWARD
THINKING ABOUT THERAPIES AND
QUALITY OF LIFE FOR PATIENTS
GETTING TREATED WITH A NUMBER OF
DIFFERENT THERAPIES.
I WOULD LIKE TO END
ACKNOWLEDGING BY WONDERFUL LAB.
IT IS A TESTAMENT TO THESE
STUDENTS WHO HAVE TAKEN A CHANCE
ON A NEW PI.
MY COLLABORATORS.
I WOULD LIKE TO HIGHLIGHT A
MEDICAL STUDENT THAT DID A LOT
OF THIS MEDICAL WORK.
LE MICHELLE WHO IS A WONDERFUL
MENTOR AND COLLABORATOR
COLLEAGUE AND THE PATIENTS AND
FAMILIES WHOSE DONATIONS OF
WHICH I COULD NOT HAVE DONE ANY
OF THIS.
LAST BUT NOT LEAST THE MARTIN
WACHTEL FAMILY AND STM, AAAS AND
THE NCI TO ALLOW ME TO SHARE MY
WORK AND HIGHLIGHT THIS FIELD AS
A WHOLE.
I THINK IT IS GOING TO BE REALLY
IMPORTANT FOR MANY OF US MOVING
FORWARD SO THANK YOU SO MUCH.
[ APPLAUSE ]
>>SO THANK YOU AGAIN, DR.
VENKATESH, FOR SUCH AN AMAZING
TALK.
REALLY INTERESTING WORK AND JUST
FASCINATING NEW AND UPCOMING
FIELD.
SO WE HAVE ABOUT 15 MINUTES FOR
QUESTIONS THAT WE CAN TAKE.
>>HI.
BEAUTIFUL TALK.
>>THANK YOU.
>>YOU ALLUDED TO THIS IN YOUR
VERY LAST SLIDE, BUT I WANTED TO
ASK, IT IS WELL KNOWN OR HAS
BECOME RECENTLY KNOWN THERE ARE
A LOT OF INTERACTIONS BETWEEN
THE NERVOUS SYSTEM AND THE
IMMUNE SYSTEM.
>>ABSOLUTELY.
>>I WAS WONDERING HOW MUCH OF
WHAT YOU DESCRIBED IS DEPENDENT
ON EFFECTS ON THE IMMUNE SYSTEM
AS WELL AS SOME OF THE DIRECT
EFFECTS YOU SHOWED BY SYNAPSES
BETWEEN NERVES AND CANCER CELLS.
>>THAT IS A GREAT QUESTION, ONE
I THINK WE ARE ALL STILL TRYING
TO UNDERSTAND.
I THINK THE REALITY OF THE
SITUATION IS IT IS GOING TO BE
VERY TUMOR DEPENDENT AND VERY
PATIENT SPECIFIC PERHAPS.
WHAT WE KNOW NOW IS THE BROAD
OVERVIEW IS THIS IDEA THAT THE
NERVOUS SYSTEM CERTAINLY SHOULD
BE LOOKED AT AND THOUGHT ABOUT
IN THE TUMOR MICROENVIRONMENT,
NOT ONLY FOR DIRECT INTERACTIONS
WITH TUMOR CELLS, BUT THE REMOLD
ELS OF THE IMMUNE SYSTEM THAT
ARE IN THAT SPACE.
THERE HAVE BEEN BEAUTIFUL PAPERS
RECENTLY ILLUSTRATED THAT
SENSORY NEURONS PLAY A HUGE ROLE
IN CREATING THIS
IMMUNOSUPPRESSIVE
MICROENVIRONMENT SO ONCE YOUING
A ROW GAIT THE SENSORY NEURONS
YOU CAN REACTIVATE THE IMMUNE
SYSTEM.
HOW IMPORTANT THESE DIFFERENT
AXES ARE GOING TO BE IS VERY
HIGHLY DEPENDENT ON THE TISSUE
TYPE, THE GENETIC ABERRATIONS
SPECIFIC TO THAT TUMOR.
SUB POPULATIONS THERE IS SO MUCH
CELL LOU LAR PLASTICITY.
THERE MIGHT BE DIFFERENT AXES
TAKING THE REINS AND PRIMARY
FOCUS.
THERE IS A LOT TO BE UNDERSTOOD,
BUT I THINK ALL WE CAN SAY IS
ALL OF THESE DIFFERENT AXES NEED
TO BE STUDIED.
AS WE MOVE FORWARD WE MIGHT HAVE
A BETTER UNDERSTANDING OF WHEN
AND WHERE AND HOW WE COULD
TARGET THESE DIFFERENT
INTERACTIONS, NEURAL SUB
POPULATIONS AND AXES BASED ON
TUMOR TIME, STAGE, PROGRESSION,
TISSUE TYPE, PATIENT AND ALL OF
THAT.
>>OKAY.
ONE VERY SIMPLE WAY IS TO
COMPARE SOME OF YOUR XENOGRAFT
MODELS WHERE THERE IS NO IMMUNE
SYSTEM.
>>WE ARE DOING THAT RIGHT NOW.
>>WITH THE -- WHAT HAPPENS IN
THE INTACT MOUSE.
>>ABSOLUTELY.
ONGOING.
I WILL SOON HAVE DATA FOR YOU ON
THAT.
BUT, YEAH, I THINK ESPECIALLY
THE EFFECT IN THE PERIPHERY, WE
SEE IT IN SMALL CELL LUNG
CANCER.
OTHER PEOPLE HAVE SHOWN IT IN
GASTRIC CANCERS IS CERTAINLY
ALMOST GOING TO HAVE SOME IMMUNE
COMPONENT TO IT.
I BELIEVE THESE ELECTRICAL,
DIRECT ELECTRICAL COMMUNICATION
IS PLAYING SOME IMPORTANT ROLE,
WHETHER THAT IS NOT DIRECTLY
GROWTH PROMOTING OR WHETHER OR
NOT THAT IS TRANSITIONING IN
TERMS OF HELPING AS WE DISCUSSED
EARLIER, WHETHER THAT IS PERHAPS
SIGNALLING TO THE TUMOR CELLS TO
SHIFT AND MOVING THEM INTO A
DIFFERENT CELLULAR STATE TO
EVADE SPECIFIC THERAPIES WE ARE
NOT YET SURE BUT IMPORTANT TO
THINK ABOUT.
>>SURE.
>>THANK YOU.
>>REALLY AMAZING WORK.
I HAVE ONE QUESTION.
DO YOU THINK YOUR WORK INDICATE
THAT PEOPLE WHO GOT DEPRESSED
HAVE A HIGHER RISK OF GETTING
CANCER?
>>NO.
I THINK THAT -- I THINK THERE IS
NOT -- WE CAN'T SAY ENOUGH ABOUT
IT JUST YET, I THINK.
WE HAVE TO REALLY UNDERSTAND THE
MECHANISMS THROUGH WHICH ALL OF
THIS IS HAPPENING.
I DON'T THINK IT IS AS CLEAR AS
THERE HAVE BEEN EPIDEMIOLOGICAL
STUDIES TO UNDERSTAND WHETHER OR
NOT WE CAN DRAW SOME CORRELATION
BETWEEN DIFFERENT
NEURODEGENERATIVE DISEASES,
DIFFERENT BRAIN CANCER
MALIGNANCIES TO SEE WHETHER OR
NOT THE STATE OF THE BRAIN CAN
BE KIND OF -- INDICATE WHETHER
YOU ARE MORE SUSCEPTIBLE TO ONE
OR THE OTHER.
RETROSPECTIVE STUDIES THAT ARE
NOT THE CLEANEST OF DATA SETS.
I THINK THERE ARE SOME VERY
INTERESTING STUDIES COMING OUT
THAT SUGGEST IF YOU ARE PRONE TO
SOME TYPE OF NEURODEGENERATIVE
DISEASES CAN BE PROTECTIVE
AGAINST CANCERS.
WE HAVE TO UNDERSTAND THE
DISTINCT MECHANISMS TO
UNDERSTAND IF THAT IS GOING TO
BE TRUE AND ALSO REALLY
SPECIFICALLY THINK ABOUT, AGAIN,
THIS IS GOING TO BE CONTEXT
SPECIFIC TO SPECIFIC N F1 TUMORS
OR P # 50 TUMORS.
ELECTRICAL ABERRATIONS WILL PLAY
A CRITICAL ROLE IN THIS
UNDERSTANDING AS WELL.
>>IT WAS SUCH AN EXCITING TALK.
I HAD A SIMILAR QUESTION GIVEN
NONNEURONAL CELLS CAN EXPRESS
AMPA RECEPTORS.
MY SECOND QUESTION WAS THAT YOU
MENTIONED THAT THE SMALL CELL
LUNG CANCER MIGHT HAVE A NEURAL
ENDOCRINE BACKGROUND.
I WONDER IF THERE WAS EVIDENCE
PERIPHERAL TUMORS MORE LILY
INNERVATED HAD SELECTIVE
ADVANTAGE FOR BRAIN METATASES.
>>THAT IS ONGOING.
IT DOESN'T LOOK LIKE THEY ARE
SPECIFIC TO THE BRAIN, BUT THERE
ARE SPECIFIC SUB POPULATIONS OF
THESE TUMORS RELYING UPON NEURAL
INPUT.
THE BRAIN HAS A VERY SPECIFIC
POPULATION OF NEURONS.
MY HYPOTHESIS WOULD BE MELANOMAS
AND LUNG CANCERS AND BREAST
CANCERS SEEM TO DERIVE THESE
INPUTS AND THEREFORE ALLOW
THEMSELVES TO THRIVE IN THE
BRAIN.
THINGS LIKE THE PANCREATIC
CANCER AND PROSTATE CANCERS MAY
BE MORE RELIANT UPON ADONERGI
KRRK SIGNALLING AND TEND TO -- A
LOT OF THIS IS NEURAL POPULATION
SPECIFIC AND TISSUE SPECIFIC.
TEASING THOSE APART ARE GOING TO
BE VERY, VERY DIFFICULT, BUT
VERY FASCINATING AND I THINK WE
ARE ON OUR WAY TO DOING THAT.
WE HAVE GENETIC MODELS TO PROBE
DIFFERENT SUB POPULATIONS.
WE ARE ACTIVELY DOING A LOT OF
SYNAPTIC TRACING TO UNDERSTAND
WHAT SUB POPULATIONS ARE
IMPORTANT.
THAT SHOULD GIVE US A MORE CLEAR
UNDERSTANDING OF WHICH
POPULATIONS TO TARGET, BUT THAT
TAKES ME TO YOUR FIRST QUESTION,
AS I MENTIONED, I THINK WE
HAVEN'T APPRECIATED THE NERVOUS
SYSTEM NOT ONLY IN THE CONTEXT
OF MALIGNANT CANCERS BUT A LOT
OF NONNEURONAL CELL TYPES.
THIS NEURAL ACCESS IS A HOT
TOPIC AND A LOT OF NOT ONLY
DISEASE PATHOLOGIES BUT IN
NORMAL DEVELOPMENT AND
UNDERSTANDING HOW DO THESE
IMMUNE CELLS, FINE RO BLASTS,
MACROFAGES, HOW ARE THEY
RESPONDING TO THESE
NEUROTRANSMITTERS?
THEY ARE INDEED RESPONDING.
UNDERSTANDING HOW THAT SHAPING
THE MICROENVIRONMENT IS GOING TO
BE VERY INTERESTING AND THAT IS
ANOTHER REASON WHY QUESTION NEED
TO RECIPROCALLY UNDERSTAND THE
ACTIVITY.
IT SEEMS THE NEURONAL ACTIVITY
IS CHANGES.
IS THE MAKEUP OF THE NEURONS
DIFFERENT?
ARE THEY BEING ACTIVATED IN A
DIFFERENT WAY?
ARE THEIR FREQUENCY PATTERNS
DIFFERENT?
THAT IS UNKNOWN SO THAT IS
EXCITING TO THINK ABOUT MOVING
FORWARD.
>>IT IS REALLY EXCITING.
THANK YOU.
>>THANK YOU.
>>FASCINATING TALK.
I HAVE A QUESTION ABOUT THE GAP
JUNCTION DATA YOU SHOWED.
>>SURE.
>>IT IS VERY STRIKING.
I AM WONDERING IF I REMEMBER
CORRECTLY, GENETICALLY YOU
BLOCKED A GAP JUNCTION ACTIVITY.
I'M WONDERING IF PHARMACOLOGY
GET NEW DROP?
>>YEAH.
WE USED METHROPHENATE AND CBX
WHICH ARE INHIBITORS.
A LOT OF THE GAP JUNCTION
INHIBITORS IS THEY ARE VERY
DIRTY.
WE HAVE USED THOSE AND SEE A
STARK EFFECT.
SO I THINK THEY ARE AND I THINK
IN GERMANY, THEY HAVE A TRIAL
TRYING TO COMBINE THE DRUG WITH
OTHER NEUROMODULATED AGENTS TO
TREAT GLIOMAS FOR THIS REASON.
THAT WILL BE EXCITING DATA TO
SEE HOW THAT COMES OUT.
WHAT WE KNOW IS THE GAP
JUNCTIONS ARE CLEARLY PLAYING A
ROLE, HOW TO TARGET THEM I THINK
IS UP FOR DEBATE BECAUSE THERE
IS A LOT OF CONTROVERSY AS TO
THE SPECIFICITY OF THE CURRENTLY
AVAILABLE INHIBITORS.
>>THANK YOU.
>>OVER HERE.
>>THANKS FOR A GREAT TALK.
I HAVE A VERY BASIC BIOLOGY
QUESTION.
IS THERE ANY ASSOCIATION BETWEEN
ANY OF YOUR MEASUREMENTS AND
WHERE THE MICE ARE IN THEIR
SLEEP/WAKE CYCLE?
>>AWESOME QUESTION.
BECAUSE LUCKILY FOR ME WHEN I
WAS DOING THIS A POSTDOC WAS
INTERESTED IN CIRCADIAN CYCLE.
I CAN'T TELL YOU IF THERE IS
DIFFERENT.
WE HAVE TIMED OUR EXPERIMENTS TO
BE MORNING EXPERIMENTS.
WE CONTROLLED FOR IT.
I'M NOT SURE.
AS YOU KNOW, THIS IDEA OF TIMING
CHEMOTHERAPIES IS BECOMING A
VERY HOT TOPIC.
I ENVISION THIS MIGHT BE
IMPORTANT.
MY COLLEAGUE IS ACTUALLY, YOU
KNOW, HAS FOUND HER LAB ON HER
OWN AND FOUND THESE PRECURSOR
CELLS THEMSELVES HAVE A VERY --
RESPOND VERY ROBUSTLY TO
NEURONAL INPUT BASED UPON THE
TIME OF DAY.
AND SO GLIOMA CELLS THINKING
ABOUT NORMAL DEVELOPMENT IT IS A
HIGH POSSIBILITY THEY SIMILARLY
RESPOND BASED ON THE TIME OF
DAY.
WE HAVE NOT TESTED THE
HYPOTHESIS.
>>WHAT WOULD BE THE
IMPLICATIONS FOR SCHEDULING
TREATMENT?
>>I COULDN'T TELL YOU UNTIL I
FOUND OUT EXACTLY AT WHICH POINT
IN TIME I FELT THE NEURAL
ACTIVITY WAS PLAYING AN
IMPORTANT ROLE.
AT WHICH POINT WAS IT HAVING ITS
BIGGEST EFFECT.
WE HAVE DONE OUR EXPERIMENTS
LARGELY IN THE MORNING TO
CONTROL FOR THAT, BUT WE DON'T
KNOW, WOULD IT BE A MORE DRASTIC
EFFECT OR LESS DRASTIC EFFECT AT
A DIFFERENT PHASE IN THE MOUSE
CYCLE.
WHETHER OR NOT THAT CORRELATES
TO THE HUMAN CYCLE IS A WHOLE
OTHER QUESTION SO WE HAVE A LOT
OF TESTING TO DO.
THAT COULD BE VERY EASILY TO DO
ON EEGs IN PATIENTS.
IT IS A TESTABLE HYPOTHESIS.
>>AND WE'LL TAKE THE LAST
QUESTION HERE.
>>GREAT TALK.
SO MY QUESTION IS MORE
CLINICALLY BASED AND ONE OF THE
CHARACTERISTICS OF MALIGNANT
GLIOMA IS THEY DON'T SPREAD
SYSTEMICALLY.
>>MM-HMM.
>>BASED ON YOUR DATA, VERY
COMPELLING THAT THEY SEEM TO
THRIVE IN BRAIN AND NERVOUS
TISSUE.
WHAT HAPPENS OR WHAT WOULD YOU
SPECULATE WOULD HAPPEN IF YOU DO
MODULATE THAT AND YOU DO -- I
MEAN, YOU DON'T CURE THE ANIMALS
BUT PROLONG SURVIVAL AND WHAT
ARISES SEEMS TO BE GLIOMA CELLS
THAT DON'T REQUIRE THE NEURONAL
INPUT.
ARE YOU CHANGING THE CANCER
BIOLOGY?
WOULD YOU SAY THAT SYSTEMIC
METATASES WOULD OCCUR?
WE KNOW GLIOMA CELLS GET INTO
CIRCULATION.
THEY ARE HARD TO FIND, BUT THEY
ARE THERE.
THEY JUST CAN'T FIND THE RIGHT
SOIL.
>>RIGHT.
>>ANY THOUGHTS ABOUT THAT
MECHANISM OF RESISTANCE AND WHAT
IT WOULD IMPLY AS WE MOVE
FORWARD INTO CLINICAL TESTING.
>>IT IS AN INTERESTING
QUESTION.
SO I THINK THAT, YOU KNOW, THE
BRAIN, THE ONLY WAY FOR ME TO
ANSWER THAT QUESTION IS THE
BRAIN MICROENVIRONMENT IS
OBVIOUSLY VERY, VERY SPECIFIC.
IT HAS ONE LARGE COMPONENT OF IT
IS THESE NEURONS AND NEURONAL
INPUTS THAT ARE IMPORTANT TO
DISEASE BIOLOGY.
BUT THERE IS ALSO SO MANY MORE
VERY BRAIN SPECIFIC CELLS THAT
ARE HIGHLY SUPPORTIVE AND I
THINK THAT CREATES THIS NICHE
THAT ALLOWS THESE TUMOR CELLS TO
THRIVE.
UNDERSTANDING A BETTER WAY TO
UNDERSTAND THIS QUESTION OF
RELIANCE UPON SEED VERSUS SOIL
IS ACTUALLY PROBABLY THINKING
ABOUT THE OTHER CELL TYPES FROM
THE PERIPHERY THAT CAN GET INTO
THE BRAIN.
TO REALLY UNDERSTAND HOW, WHAT
MIGHT BE HAPPENING THERE.
THERE ARE U87, DIFFERENT MODELS
OF GLIOMAS OUT THERE PERPETUATED
FOR YEARS AND YEARS AND YEARS
THAT HAVE DEVELOPED SO MANY
MUTATIONS YOU CAN INJECT IN A
MOUSE THEY WILL GROW.
I DON'T THINK THOSE CELLS ARE
ANY LONGER RELIANT UPON THIS
NEURONAL INPUT.
THEY HAVE ENOUGH MUTATIONS TO
SURVIVE ON THEIR OWN AND
OVERRIDE ANY OF THESE EXTERNAL
CUES.
I THINK, YOU KNOW, UNDERSTANDING
EXACTLY THE DIFFERENT CELLULAR
POPULATIONS AND INPUTS FROM
OTHER CELL, OTHER MALIGNANCIES
IN THE BODY THAT ALLOW THEM TO
THRIVE WITHIN THE BRAIN MAY GIVE
US INSIGHT INTO THE CELLULAR SUB
POPULATIONS AND UP REGULATION OF
SPECIFIC RECEPTORS THAT DO ALLOW
METASTASES.
HOW DO WE STOP THE SPREAD OF THE
DISEASE BECAUSE THAT IS WHAT
ULTIMATELY KILLS THESE PATIENTS.
THIS IS A SEED-AND-SOIL QUESTION
AND PREVENT THESE CELLS FROM
KIND OF GAINING THE ABILITY TO
THRIVE IN A COMPLETELY DIFFERENT
ORGAN WILL BASEBALL TO STOP THAT
SUSCEPTIBILITY.
THE NERVOUS SYSTEM IS LIKELY ONE
COMPONENT OF THAT.
THERE ARE OTHER TISSUE SPECIFIC
INTERACTIONS WE LIKELY NEED TO
TARGET AND THINK ABOUT.
IT COMES BACK TO THINKING ABOUT
THESE CANCERS VERY HOLISTICALLY.
I DON'T KNOW IF THAT ANSWERS
YOUR QUESTION?
>>AS A CLINICAL INVESTIGATOR,
WE ARE ALWAYS CONCERNED AND
THERE IS A NATURAL EXPERIMENT
THAT HAS GONE ON FOR DECADES
WHICH IS WHEN PATIENTS WITH
GLIOMA DEVELOP HYDROCEPHALIS AND
SHUNTING CELL.
AT AUTOPSY YOU DON'T FIND TUMOR
MASSES.
YOU FIND TINY NODULES OF CANCER.
THEY JUST CAN'T THRIVE.
>>RIGHT.
>>I WONDER HOW MUCH OF THAT IS
THE SOIL AND WHETHER CHANGING IT
MAKES THEM MORE ADAPTABLE, BUT
WE'LL KNOW.
IT WOULD BE INTERESTING TO SEE
WHEN WE START DOING THE CLINICAL
WORK, WHEN PATIENTS GET THESE
THERAPIES WHAT THEIR TUMOR LOOKS
LIKE AND HOW THEY HAVE CHANGED.
>>YEAH.
ABSOLUTELY.
THE ONE THING THAT IS VERY
CLEAR, IF YOU TAKE ANY
SEQUENCING FROM PATIENTS THAT
HAVE DEVELOPED BRAIN METS THERE
ASTASES AND COMPARE TO PRIMARY
TISSUE, ACROSS THE BOARD THEY
SEEM TO UP REGULATE ION CHANNEL
RECEPTORS THAT ALLOW THEM TO
THRIVE IN THE BRAIN.
WE PROBED FOR THE
NEUROTRANSMITTER RECEPTORS BUT
IN TERMS OF SPECIFIC MICROGLIAL
CUES OR OTHER CELLS.
THEY ARE PLASTIC CELLS AND
ADAPTS IN AN IMPORTANT WAY AND
THINKING ABOUT THAT IS VERY
IMPORTANT.
THAT IS A GREAT QUESTION.
>>THANK YOU.
>>THANK YOU, DR. VENKATESH.
>>YEAH.
THANK YOU.
>>CONGRATULATIONS.
>>THANK YOU SO MUCH TO
EVERYBODY AND THANK YOU FOR YOUR
TIME AND ATTENTION.
>>I WANT TO SAY A BIG THANK YOU
TO EVERYONE WHO CAME TODAY.
PLEASE DO SPREAD THE WORD ABOUT
THIS AWARD.
NEW INVESTIGATORS CAN APPLY FOR
THE 2024 WACHTEL AWARD.
I BELIEVE APPLICATION IS OPEN
MID SEPTEMBER.
AND THEN FOR EVERYONE IN PERSON,
PLEASE DO JOIN US FOR LUNCH IN
THE FAES TERRACE.
AND THERE ARE COPIES OF DR.
VENKATESH'S ESSAY OUT FRONT, I
BELIEVE.
YEAH.
SO PLEASE TAKE ONE.