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Project Grant R01CA229580
Award Date
7/12/18
Completion Date
6/30/23
Dollars Obligated
$5.6M
Overview
Activity
26
Transactions
34
Subawards
Federal Agency
National Cancer Institute
Awardee
Sloan-Kettering Institute For Cancer Research (KUKXRCZ6NZC2)
Federal Grant Program
93.396
Assistance Type
Project Grant
Place of Performance
New York, USA
Description
Update #1
IDENTIFYING AND TARGETING METABOLIC DEPENDENCIES IN THE PANCREATIC TUMOR MICROENVIRONMENT
Posted 7/12/18, 12:00 AM
Mod #
Description
Reason For Modification
Federal Obligation
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Date
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Not listed
IDENTIFYING AND TARGETING METABOLIC DEPENDENCIES IN THE PANCREATIC TUMOR MICROENVIRONMENT - PROJECT SUMMARY/ABSTRACT PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) CELLS MAINTAIN PROLIFERATIVE CAPACITY DESPITE A HYPOVASCULAR, NUTRIENT- POOR MICROENVIRONMENT; THIS CHALLENGING MICROENVIRONMENT IS ESTABLISHED BY CANCER-ASSOCIATED FIBROBLASTS (CAFS). PDAC CAFS ARE PREDOMINANTLY DERIVED FROM PANCREATIC STELLATE CELLS (PSCS), LIPID-STORING CELLS IN HEALTHY PANCREAS WHICH CAN TRANSDIFFERENTIATE TO AN ACTIVATED CAF PHENOTYPE AND GENERATE A DENSE, DESMOPLASTIC STROMA. CAF-DERIVED COMPONENTS GENERATE AN OXYGEN- AND NUTRIENT-POOR MICROENVIRONMENT TO WHICH PDAC CELLS MUST ADAPT. THESE ADAPTATION MECHANISMS REMAIN POORLY UNDERSTOOD, AND MAY REPRESENT VULNERABILITIES FOR THERAPEUTIC INTERVENTION. OUR RECENT RESULTS SUGGEST THAT PARACRINE LIPID FLUX FROM PSC-DERIVED CAFS REPRESENTS A NOVEL MECHANISM BY WHICH THE STROMA PROVIDES ENERGY AND PRO-PROLIFERATIVE SIGNALS TO CANCER CELLS TO SUPPORT PDAC GROWTH. SPECIFICALLY, WE FIND THAT PDAC CAFS SECRETE ABUNDANT LYSOPHOSPHATIDYLCHOLINE (LPC), THE PREFERRED FATTY ACID SCAVENGING SUBSTRATE FOR RAS-TRANSFORMED CELLS SUCH AS PDAC CELLS; THE PDAC CAF SECRETOME ALSO CONTAINS HIGH LEVELS OF LYSOPHOSPHATIDIC ACID (LPA), AN ESTABLISHED MITOGEN WITH MULTIPLE DOWNSTREAM EFFECTORS WITH ROLES IN TUMORIGENESIS. OUR PRELIMINARY TRANSCRIPTIONAL AND LIPIDOMIC DATA SUGGEST THAT PSCS UNDERGO A DRAMATIC LIPID METABOLIC SHIFT IN THE CONTEXT OF PANCREATIC TUMORIGENESIS, INCLUDING REMODELING OF THE INTRACELLULAR LIPIDOME AND SECRETION OF ABUNDANT LIPIDS IN THE ACTIVATED CAF STATE. THESE RESULTS RAISE THE POSSIBILITY THAT PDAC CAFS SECRETE SPECIFIC LIPID SPECIES THAT ACT IN A PARACRINE MANNER TO "FEED" THE EPITHELIAL COMPARTMENT AND STIMULATE PROLIFERATION. WE HYPOTHESIZE THAT FIBROBLASTIC CELLS FUNCTION VIA SECRETED LIPIDS TO PROMOTE EPITHELIAL CELL PROLIFERATION AND SURVIVAL IN THE CONTEXT OF AN INHOSPITABLE WOUND-HEALING RESPONSE. THIS HYPOTHESIS WILL BE TESTED WITH THE FOLLOWING SPECIFIC AIMS. AIM 1: UNDERSTAND THE EFFECT OF STROMA-DERIVED LIPIDS ON CANCER CELL LIPID METABOLISM. A STABLE ISOTOPE TRACING APPROACH WILL BE USED TO DETERMINE THE EXTENT OF PARACRINE METABOLIC FLUX FROM STROMAL CELLS TO CANCER CELLS AMONG SECRETED LIPIDS, AND ALTERATIONS TO PDAC CELL METABOLISM IN RESPONSE TO STROMA-DERIVED LIPIDS WILL BE ASSESSED USING ESTABLISHED METABOLIC ASSAYS. AIM 2: DETERMINE THE ROLE OF STROMA-DERIVED LIPIDS IN PDAC CELL GROWTH CONTROL. ESTABLISHED IN VITRO CULTURE AND CO-CULTURE SYSTEMS WILL BE USED TO ANALYZE REGULATION OF MITOGENIC LPA EFFECTORS PATHWAYS AND GROWTH CAPACITY IN RESPONSE TO STROMA-DERIVED LIPIDS. AIM 3: DEFINE THE SIGNIFICANCE OF THE LPC-AUTOTAXIN-LPA AXIS IN MICROENVIRONMENTAL REGULATION OF PANCREATIC CANCER GROWTH IN VIVO. LPA IS GENERATED FROM LPC BY SECRETED ENZYME AUTOTAXIN; WE FIND THAT LPC IS SECRETED AT HIGH LEVELS BY PDAC CAFS, AND THAT ATX IS OVEREXPRESSED IN MOUSE AND HUMAN PDAC. THE LPC-AUTOTAXIN-LPA AXIS WILL BE INTERROGATED BOTH GENETICALLY AND PHARMACOLOGICALLY IN A PDAC MOUSE MODEL IN VIVO TO DETERMINE ITS ROLE IN PDAC PROGRESSION. THESE STUDIES WILL IMPROVE OUR UNDERSTANDING OF PDAC CELL SURVIVAL AND GROWTH MECHANISMS IN THE CONTEXT OF A NUTRIENT-POOR TUMOR MICROENVIRONMENT, POTENTIALLY IDENTIFYING A NOVEL ROUTE FOR THERAPEUTIC INTERVENTION.
($1k)
1/15/25
Not listed
IDENTIFYING AND TARGETING METABOLIC DEPENDENCIES IN THE PANCREATIC TUMOR MICROENVIRONMENT - PROJECT SUMMARY/ABSTRACT PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) CELLS MAINTAIN PROLIFERATIVE CAPACITY DESPITE A HYPOVASCULAR, NUTRIENT- POOR MICROENVIRONMENT; THIS CHALLENGING MICROENVIRONMENT IS ESTABLISHED BY CANCER-ASSOCIATED FIBROBLASTS (CAFS). PDAC CAFS ARE PREDOMINANTLY DERIVED FROM PANCREATIC STELLATE CELLS (PSCS), LIPID-STORING CELLS IN HEALTHY PANCREAS WHICH CAN TRANSDIFFERENTIATE TO AN ACTIVATED CAF PHENOTYPE AND GENERATE A DENSE, DESMOPLASTIC STROMA. CAF-DERIVED COMPONENTS GENERATE AN OXYGEN- AND NUTRIENT-POOR MICROENVIRONMENT TO WHICH PDAC CELLS MUST ADAPT. THESE ADAPTATION MECHANISMS REMAIN POORLY UNDERSTOOD, AND MAY REPRESENT VULNERABILITIES FOR THERAPEUTIC INTERVENTION. OUR RECENT RESULTS SUGGEST THAT PARACRINE LIPID FLUX FROM PSC-DERIVED CAFS REPRESENTS A NOVEL MECHANISM BY WHICH THE STROMA PROVIDES ENERGY AND PRO-PROLIFERATIVE SIGNALS TO CANCER CELLS TO SUPPORT PDAC GROWTH. SPECIFICALLY, WE FIND THAT PDAC CAFS SECRETE ABUNDANT LYSOPHOSPHATIDYLCHOLINE (LPC), THE PREFERRED FATTY ACID SCAVENGING SUBSTRATE FOR RAS-TRANSFORMED CELLS SUCH AS PDAC CELLS; THE PDAC CAF SECRETOME ALSO CONTAINS HIGH LEVELS OF LYSOPHOSPHATIDIC ACID (LPA), AN ESTABLISHED MITOGEN WITH MULTIPLE DOWNSTREAM EFFECTORS WITH ROLES IN TUMORIGENESIS. OUR PRELIMINARY TRANSCRIPTIONAL AND LIPIDOMIC DATA SUGGEST THAT PSCS UNDERGO A DRAMATIC LIPID METABOLIC SHIFT IN THE CONTEXT OF PANCREATIC TUMORIGENESIS, INCLUDING REMODELING OF THE INTRACELLULAR LIPIDOME AND SECRETION OF ABUNDANT LIPIDS IN THE ACTIVATED CAF STATE. THESE RESULTS RAISE THE POSSIBILITY THAT PDAC CAFS SECRETE SPECIFIC LIPID SPECIES THAT ACT IN A PARACRINE MANNER TO "FEED" THE EPITHELIAL COMPARTMENT AND STIMULATE PROLIFERATION. WE HYPOTHESIZE THAT FIBROBLASTIC CELLS FUNCTION VIA SECRETED LIPIDS TO PROMOTE EPITHELIAL CELL PROLIFERATION AND SURVIVAL IN THE CONTEXT OF AN INHOSPITABLE WOUND-HEALING RESPONSE. THIS HYPOTHESIS WILL BE TESTED WITH THE FOLLOWING SPECIFIC AIMS. AIM 1: UNDERSTAND THE EFFECT OF STROMA-DERIVED LIPIDS ON CANCER CELL LIPID METABOLISM. A STABLE ISOTOPE TRACING APPROACH WILL BE USED TO DETERMINE THE EXTENT OF PARACRINE METABOLIC FLUX FROM STROMAL CELLS TO CANCER CELLS AMONG SECRETED LIPIDS, AND ALTERATIONS TO PDAC CELL METABOLISM IN RESPONSE TO STROMA-DERIVED LIPIDS WILL BE ASSESSED USING ESTABLISHED METABOLIC ASSAYS. AIM 2: DETERMINE THE ROLE OF STROMA-DERIVED LIPIDS IN PDAC CELL GROWTH CONTROL. ESTABLISHED IN VITRO CULTURE AND CO-CULTURE SYSTEMS WILL BE USED TO ANALYZE REGULATION OF MITOGENIC LPA EFFECTORS PATHWAYS AND GROWTH CAPACITY IN RESPONSE TO STROMA-DERIVED LIPIDS. AIM 3: DEFINE THE SIGNIFICANCE OF THE LPC-AUTOTAXIN-LPA AXIS IN MICROENVIRONMENTAL REGULATION OF PANCREATIC CANCER GROWTH IN VIVO. LPA IS GENERATED FROM LPC BY SECRETED ENZYME AUTOTAXIN; WE FIND THAT LPC IS SECRETED AT HIGH LEVELS BY PDAC CAFS, AND THAT ATX IS OVEREXPRESSED IN MOUSE AND HUMAN PDAC. THE LPC-AUTOTAXIN-LPA AXIS WILL BE INTERROGATED BOTH GENETICALLY AND PHARMACOLOGICALLY IN A PDAC MOUSE MODEL IN VIVO TO DETERMINE ITS ROLE IN PDAC PROGRESSION. THESE STUDIES WILL IMPROVE OUR UNDERSTANDING OF PDAC CELL SURVIVAL AND GROWTH MECHANISMS IN THE CONTEXT OF A NUTRIENT-POOR TUMOR MICROENVIRONMENT, POTENTIALLY IDENTIFYING A NOVEL ROUTE FOR THERAPEUTIC INTERVENTION.
($157k)
1/15/25
Not listed
IDENTIFYING AND TARGETING METABOLIC DEPENDENCIES IN THE PANCREATIC TUMOR MICROENVIRONMENT - PROJECT SUMMARY/ABSTRACT PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) CELLS MAINTAIN PROLIFERATIVE CAPACITY DESPITE A HYPOVASCULAR, NUTRIENT- POOR MICROENVIRONMENT; THIS CHALLENGING MICROENVIRONMENT IS ESTABLISHED BY CANCER-ASSOCIATED FIBROBLASTS (CAFS). PDAC CAFS ARE PREDOMINANTLY DERIVED FROM PANCREATIC STELLATE CELLS (PSCS), LIPID-STORING CELLS IN HEALTHY PANCREAS WHICH CAN TRANSDIFFERENTIATE TO AN ACTIVATED CAF PHENOTYPE AND GENERATE A DENSE, DESMOPLASTIC STROMA. CAF-DERIVED COMPONENTS GENERATE AN OXYGEN- AND NUTRIENT-POOR MICROENVIRONMENT TO WHICH PDAC CELLS MUST ADAPT. THESE ADAPTATION MECHANISMS REMAIN POORLY UNDERSTOOD, AND MAY REPRESENT VULNERABILITIES FOR THERAPEUTIC INTERVENTION. OUR RECENT RESULTS SUGGEST THAT PARACRINE LIPID FLUX FROM PSC-DERIVED CAFS REPRESENTS A NOVEL MECHANISM BY WHICH THE STROMA PROVIDES ENERGY AND PRO-PROLIFERATIVE SIGNALS TO CANCER CELLS TO SUPPORT PDAC GROWTH. SPECIFICALLY, WE FIND THAT PDAC CAFS SECRETE ABUNDANT LYSOPHOSPHATIDYLCHOLINE (LPC), THE PREFERRED FATTY ACID SCAVENGING SUBSTRATE FOR RAS-TRANSFORMED CELLS SUCH AS PDAC CELLS; THE PDAC CAF SECRETOME ALSO CONTAINS HIGH LEVELS OF LYSOPHOSPHATIDIC ACID (LPA), AN ESTABLISHED MITOGEN WITH MULTIPLE DOWNSTREAM EFFECTORS WITH ROLES IN TUMORIGENESIS. OUR PRELIMINARY TRANSCRIPTIONAL AND LIPIDOMIC DATA SUGGEST THAT PSCS UNDERGO A DRAMATIC LIPID METABOLIC SHIFT IN THE CONTEXT OF PANCREATIC TUMORIGENESIS, INCLUDING REMODELING OF THE INTRACELLULAR LIPIDOME AND SECRETION OF ABUNDANT LIPIDS IN THE ACTIVATED CAF STATE. THESE RESULTS RAISE THE POSSIBILITY THAT PDAC CAFS SECRETE SPECIFIC LIPID SPECIES THAT ACT IN A PARACRINE MANNER TO "FEED" THE EPITHELIAL COMPARTMENT AND STIMULATE PROLIFERATION. WE HYPOTHESIZE THAT FIBROBLASTIC CELLS FUNCTION VIA SECRETED LIPIDS TO PROMOTE EPITHELIAL CELL PROLIFERATION AND SURVIVAL IN THE CONTEXT OF AN INHOSPITABLE WOUND-HEALING RESPONSE. THIS HYPOTHESIS WILL BE TESTED WITH THE FOLLOWING SPECIFIC AIMS. AIM 1: UNDERSTAND THE EFFECT OF STROMA-DERIVED LIPIDS ON CANCER CELL LIPID METABOLISM. A STABLE ISOTOPE TRACING APPROACH WILL BE USED TO DETERMINE THE EXTENT OF PARACRINE METABOLIC FLUX FROM STROMAL CELLS TO CANCER CELLS AMONG SECRETED LIPIDS, AND ALTERATIONS TO PDAC CELL METABOLISM IN RESPONSE TO STROMA-DERIVED LIPIDS WILL BE ASSESSED USING ESTABLISHED METABOLIC ASSAYS. AIM 2: DETERMINE THE ROLE OF STROMA-DERIVED LIPIDS IN PDAC CELL GROWTH CONTROL. ESTABLISHED IN VITRO CULTURE AND CO-CULTURE SYSTEMS WILL BE USED TO ANALYZE REGULATION OF MITOGENIC LPA EFFECTORS PATHWAYS AND GROWTH CAPACITY IN RESPONSE TO STROMA-DERIVED LIPIDS. AIM 3: DEFINE THE SIGNIFICANCE OF THE LPC-AUTOTAXIN-LPA AXIS IN MICROENVIRONMENTAL REGULATION OF PANCREATIC CANCER GROWTH IN VIVO. LPA IS GENERATED FROM LPC BY SECRETED ENZYME AUTOTAXIN; WE FIND THAT LPC IS SECRETED AT HIGH LEVELS BY PDAC CAFS, AND THAT ATX IS OVEREXPRESSED IN MOUSE AND HUMAN PDAC. THE LPC-AUTOTAXIN-LPA AXIS WILL BE INTERROGATED BOTH GENETICALLY AND PHARMACOLOGICALLY IN A PDAC MOUSE MODEL IN VIVO TO DETERMINE ITS ROLE IN PDAC PROGRESSION. THESE STUDIES WILL IMPROVE OUR UNDERSTANDING OF PDAC CELL SURVIVAL AND GROWTH MECHANISMS IN THE CONTEXT OF A NUTRIENT-POOR TUMOR MICROENVIRONMENT, POTENTIALLY IDENTIFYING A NOVEL ROUTE FOR THERAPEUTIC INTERVENTION.
$1.0k
1/15/25
Not listed
IDENTIFYING AND TARGETING METABOLIC DEPENDENCIES IN THE PANCREATIC TUMOR MICROENVIRONMENT - PROJECT SUMMARY/ABSTRACT PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) CELLS MAINTAIN PROLIFERATIVE CAPACITY DESPITE A HYPOVASCULAR, NUTRIENT- POOR MICROENVIRONMENT; THIS CHALLENGING MICROENVIRONMENT IS ESTABLISHED BY CANCER-ASSOCIATED FIBROBLASTS (CAFS). PDAC CAFS ARE PREDOMINANTLY DERIVED FROM PANCREATIC STELLATE CELLS (PSCS), LIPID-STORING CELLS IN HEALTHY PANCREAS WHICH CAN TRANSDIFFERENTIATE TO AN ACTIVATED CAF PHENOTYPE AND GENERATE A DENSE, DESMOPLASTIC STROMA. CAF-DERIVED COMPONENTS GENERATE AN OXYGEN- AND NUTRIENT-POOR MICROENVIRONMENT TO WHICH PDAC CELLS MUST ADAPT. THESE ADAPTATION MECHANISMS REMAIN POORLY UNDERSTOOD, AND MAY REPRESENT VULNERABILITIES FOR THERAPEUTIC INTERVENTION. OUR RECENT RESULTS SUGGEST THAT PARACRINE LIPID FLUX FROM PSC-DERIVED CAFS REPRESENTS A NOVEL MECHANISM BY WHICH THE STROMA PROVIDES ENERGY AND PRO-PROLIFERATIVE SIGNALS TO CANCER CELLS TO SUPPORT PDAC GROWTH. SPECIFICALLY, WE FIND THAT PDAC CAFS SECRETE ABUNDANT LYSOPHOSPHATIDYLCHOLINE (LPC), THE PREFERRED FATTY ACID SCAVENGING SUBSTRATE FOR RAS-TRANSFORMED CELLS SUCH AS PDAC CELLS; THE PDAC CAF SECRETOME ALSO CONTAINS HIGH LEVELS OF LYSOPHOSPHATIDIC ACID (LPA), AN ESTABLISHED MITOGEN WITH MULTIPLE DOWNSTREAM EFFECTORS WITH ROLES IN TUMORIGENESIS. OUR PRELIMINARY TRANSCRIPTIONAL AND LIPIDOMIC DATA SUGGEST THAT PSCS UNDERGO A DRAMATIC LIPID METABOLIC SHIFT IN THE CONTEXT OF PANCREATIC TUMORIGENESIS, INCLUDING REMODELING OF THE INTRACELLULAR LIPIDOME AND SECRETION OF ABUNDANT LIPIDS IN THE ACTIVATED CAF STATE. THESE RESULTS RAISE THE POSSIBILITY THAT PDAC CAFS SECRETE SPECIFIC LIPID SPECIES THAT ACT IN A PARACRINE MANNER TO "FEED" THE EPITHELIAL COMPARTMENT AND STIMULATE PROLIFERATION. WE HYPOTHESIZE THAT FIBROBLASTIC CELLS FUNCTION VIA SECRETED LIPIDS TO PROMOTE EPITHELIAL CELL PROLIFERATION AND SURVIVAL IN THE CONTEXT OF AN INHOSPITABLE WOUND-HEALING RESPONSE. THIS HYPOTHESIS WILL BE TESTED WITH THE FOLLOWING SPECIFIC AIMS. AIM 1: UNDERSTAND THE EFFECT OF STROMA-DERIVED LIPIDS ON CANCER CELL LIPID METABOLISM. A STABLE ISOTOPE TRACING APPROACH WILL BE USED TO DETERMINE THE EXTENT OF PARACRINE METABOLIC FLUX FROM STROMAL CELLS TO CANCER CELLS AMONG SECRETED LIPIDS, AND ALTERATIONS TO PDAC CELL METABOLISM IN RESPONSE TO STROMA-DERIVED LIPIDS WILL BE ASSESSED USING ESTABLISHED METABOLIC ASSAYS. AIM 2: DETERMINE THE ROLE OF STROMA-DERIVED LIPIDS IN PDAC CELL GROWTH CONTROL. ESTABLISHED IN VITRO CULTURE AND CO-CULTURE SYSTEMS WILL BE USED TO ANALYZE REGULATION OF MITOGENIC LPA EFFECTORS PATHWAYS AND GROWTH CAPACITY IN RESPONSE TO STROMA-DERIVED LIPIDS. AIM 3: DEFINE THE SIGNIFICANCE OF THE LPC-AUTOTAXIN-LPA AXIS IN MICROENVIRONMENTAL REGULATION OF PANCREATIC CANCER GROWTH IN VIVO. LPA IS GENERATED FROM LPC BY SECRETED ENZYME AUTOTAXIN; WE FIND THAT LPC IS SECRETED AT HIGH LEVELS BY PDAC CAFS, AND THAT ATX IS OVEREXPRESSED IN MOUSE AND HUMAN PDAC. THE LPC-AUTOTAXIN-LPA AXIS WILL BE INTERROGATED BOTH GENETICALLY AND PHARMACOLOGICALLY IN A PDAC MOUSE MODEL IN VIVO TO DETERMINE ITS ROLE IN PDAC PROGRESSION. THESE STUDIES WILL IMPROVE OUR UNDERSTANDING OF PDAC CELL SURVIVAL AND GROWTH MECHANISMS IN THE CONTEXT OF A NUTRIENT-POOR TUMOR MICROENVIRONMENT, POTENTIALLY IDENTIFYING A NOVEL ROUTE FOR THERAPEUTIC INTERVENTION.
$157.0k
1/15/25
Not listed
FATTY ACID SIGNALING IN THE PANCREATIC TUMOR MICROENVIRONMENT - PROJECT SUMMARY/ABSTRACT DESPITE SIGNIFICANT RECENT ADVANCES IN PRECISION MEDICINE, PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) REMAINS NEAR-UNIFORMLY LETHAL. WHILE THE MOST FREQUENT GENOMIC ALTERATIONS IN PDAC ARE NOT PRESENTLY DRUGGABLE AND CONVENTIONAL THERAPIES ARE OFTEN INEFFECTIVE IN THIS DISEASE, IMMUNE-MODULATORY THERAPIES HOLD PROMISE TO MEANINGFULLY IMPROVE OUTCOMES FOR PDAC PATIENTS. DEVELOPMENT OF SUCH THERAPIES REQUIRES AN IMPROVED UNDERSTANDING OF THE IMMUNE EVASION MECHANISMS THAT CHARACTERIZE THE PDAC MICROENVIRONMENT, INCLUDING FREQUENT EXCLUSION OF ANTINEOPLASTIC T CELLS AND ABUNDANCE OF IMMUNE-SUPPRESSIVE MYELOID CELLS. WE RECENTLY FOUND THAT CANCER CELL-INTRINSIC GLUTAMIC-OXALOACETIC TRANSAMINASE 2 (GOT2) SHAPES THE IMMUNE MICROENVIRONMENT TO SUPPRESS ANTITUMOR IMMUNITY. MECHANISTICALLY, WE FOUND THAT GOT2 FUNCTIONS BEYOND ITS ESTABLISHED ROLE IN THE MALATE-ASPARTATE SHUTTLE AND PROMOTES THE TRANSCRIPTIONAL ACTIVITY OF NUCLEAR RECEPTOR PPARD, FACILITATED BY DIRECT BINDING TO PPARD LIGAND ARACHIDONIC ACID. WHILE GOT2 IN PDAC CELLS IS DISPENSABLE FOR CANCER CELL PROLIFERATION IN VIVO, GOT2 LOSS RESULTS IN T CELL-DEPENDENT SUPPRESSION OF TUMOR GROWTH, AND GENETIC OR PHARMACOLOGIC PPARD ACTIVATION RESTORES PDAC PROGRESSION IN THE GOT2-NULL CONTEXT. THIS CANCER CELL-INTRINSIC GOT2-PPARD AXIS PROMOTES SPATIAL RESTRICTION OF BOTH CD4 AND CD8 T CELLS FROM THE TUMOR MICROENVIRONMENT, AND FOSTERS THE IMMUNE-SUPPRESSIVE PHENOTYPE OF TUMOR-INFILTRATING MYELOID CELLS. OUR RESULTS TO DATE DEMONSTRATE A NON-CANONICAL FUNCTION FOR AN ESTABLISHED MITOCHONDRIAL ENZYME IN TRANSCRIPTIONAL REGULATION OF IMMUNE EVASION, AND HERE WE PROPOSE TO EXPLOIT THIS NOVEL GOT2-PPARD AXIS TO PROMOTE A PRODUCTIVE ANTITUMOR IMMUNE RESPONSE WITH THE FOLLOWING SPECIFIC AIMS. AIM 1: ASSESS THE THERAPEUTIC POTENTIAL OF TARGETING THE GOT2-PPARD AXIS IN ESTABLISHED PDAC. WE WILL PERFORM PRECLINICAL EVALUATION OF GOT2/PPARD PATHWAY INHIBITION TOGETHER WITH THERAPEUTIC APPROACHES AIMED TO INCREASE ANTITUMOR T CELL ACTIVITY IN DIVERSE MOUSE MODELS, VALIDATE OUR FINDINGS IN PATIENT SPECIMENS WITH KNOWN CLINICAL OUTCOMES AND MUTATIONAL STATUS, AND ASSESS HETEROGENEITY ACROSS THE PATIENT POPULATION WITH RESPECT TO THE ASSOCIATION BETWEEN GOT2 SIGNALING AND T CELL SPATIAL REGULATION. AIM 2: ANALYZE THE IMMUNE EVASION MECHANISMS DRIVEN BY CANCER CELL-INTRINSIC GOT2. WE WILL APPLY IN VITRO CO-CULTURE SYSTEMS, IN VIVO ASSAYS TESTING A SUITE OF GOT2 MUTANTS WITH VARYING FATTY ACID SIGNALING CAPACITY, AND UNBIASED TRANSCRIPTIONAL ANALYSES TO UNDERSTAND THE STEPWISE MECHANISMS MEDIATING PARACRINE REGULATION OF IMMUNE EVASION. AIM 3: INTERROGATE FATTY ACID-MEDIATED GENE REGULATION BY GOT2 AND PPARD. WE WILL ANALYZE THE GENOME-WIDE BINDING PATTERNS OF PPARD AND ADDITIONAL IMMUNE-MODULATORY TRANSCRIPTION FACTORS PUTATIVELY REGULATED BY GOT2, AND CHARACTERIZE CHROMATIN STATES IN THE CONTEXT OF FATTY ACID SIGNALING PERTURBATIONS THAT PREVENT OR PERMIT ANTITUMOR IMMUNE RESPONSES. THIS WORK WILL LEVERAGE OUR RECENT IDENTIFICATION OF A NOVEL IMMUNE SUPPRESSION MECHANISM IN PDAC, WITH THE POTENTIAL TO INFORM ON NEW THERAPEUTIC COMBINATIONS POISED FOR CLINICAL TRANSLATION.
$462.4k
4/24/24