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Principal Investigator: Jiyeon Kim
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $480,137
Funding agency: National Cancer Institute
PROJECT SUMMARY
Given the important roles of tumor suppressors and oncogenes in metabolic reprogramming, there is
significant translational potential in identifying and understanding how particular oncogenotypes influence tumor
metabolism, and whether these changes impose liabilities that can be exploited therapeutically. From more recent
studies, however, a nuanced picture has emerged showing that tissue context impacts the execution of metabolic
reprogramming even with the same oncogenic drivers. For example, despite having the same driver mutations,
pancreatic cancer and lung cancer exhibit differences in branched chain amino acid (BCAA) metabolism, where
lung tumors increase BCAA uptake to use them as a nitrogen source while pancreatic tumors decrease BCAA
uptake due to decreased expression of genes in BCAA metabolism compared with normal pancreas. Thus,
understanding how cell-of-origin interacts with genetic events to affect the metabolic dependence of tumors will
be critical for selecting the right treatment approaches for patients.
By analyzing the metabolome of human non-small cell lung cancer (NSCLC) samples surgically resected
from patients and comparing those with KRAS mutations (K) to those with KRAS/LKB1 co-mutations (KL), we
noted that serine-glycine one carbon (SGOC) metabolism is significantly altered in KL NSCLC, similar to KL
pancreatic cancer models. By further metabolic analyses, however, we clarified the differences in SGOC
metabolism between these two tumor types. While KL pancreatic cancer requires SGOC for DNA methylation,
KL NSCLC depends on SGOC via serine hydroxymethyltransferase (SHMT) enzymes to maintain redox
homeostasis. By establishing both molecular and metabolic platforms to measure metabolites involved in redox
balance, and utilizing clinically relevant mouse models for in vivo studies, we are now poised to define the
oncogenic role of SHMTs during lung tumorigenesis.
In Aim 1 we will interrogate the mechanistic basis of SHMT dependence in these NSCLC cells. In Aim 2
we will investigate the molecular mechanism by which LKB1 regulates SHMT. In Aim 3 we will examine 1)
whether SHMT suppression reduces tumor growth and 2) whether the combination of SHMT inhibition with
chemotherapeutic drugs that induce oxidative stress can further inhibit tumor growth using various mouse models.
While the critical role of SGOC as a methyl group donor for DNA methylation in KL pancreatic cancer has been
reported, the importance of SGOC metabolism in KL NSCLC or heterogeneity between these two diseases has
yet to be elucidated. Our studies will provide valuable information for substratification of NSCLC patients with
hyperactive SGOC metabolism as treatment responders to therapies targeting redox balance, which is pertinent
to the goals of precision medicine.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Abnormal Assessment of Metabolism><Affect><Algorithms><Allothreonine Aldolase><Aminoacetic Acid><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antioxidants><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Autoregulation><B-raf-1><BRAF><BRAF gene><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Biology><Body Tissues><Branched-Chain Amino Acids><C-K-RAS><Callicrein><Cancer Drug><Cancer Genes><Cancer Patient><Cancer-Promoting Gene><Carbon><Cell Body><Cell Communication and Signaling><Cell Death><Cell Lineage><Cell Signaling><Cells><Chemicals><Clinical><Coenzyme II><Collaborations><D-Glucose><DNA Methylation><DNA Molecular Biology><Data><Dependence><Dextrose><Disease><Disorder><Drug Targeting><Drugs><EGF Receptor><EGFR><ERBB Protein><Enzyme Gene><Enzymes><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Equilibrium><Event><Exhibits><Fatty Acids><Frequencies><G6PD><G6PD gene><G6PD1><Gene Alteration><Gene Expression><Gene Mutation><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Gln><Glucose><Glutamine><Glycine><Glycine Hydroxymethyltransferase><Goals><Growth><HER1><Heterogeneity><Homeostasis><Human><Hyperactivity><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KLK family><KLKs><KRAS><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><KRAS2><KRAS2 gene><Kallidinogenase><Kalliginogenase><Kallikreins><Ki-RAS><Kinases><Kinin-Forming Enzyme><Kininogenase><L-Glutamine><L-Serine><LKB1><LKB1/STK11 Gene><Lung Neoplasms><Lung Tumor><Malignant Cell><Malignant Pancreatic Neoplasm><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Measures><Mediating><Medication><Metabolic><Metabolic Processes><Metabolic Studies><Metabolism><Metabolism Studies><Mice><Mice Mammals><Mitochondria><Modern Man><Molecular><Molecular Biology><Murine><Mus><Mutation><NAD phosphate><NAD(H) phosphate><NADH phosphate><NADP><NADPH><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neoplastic Disease Chemotherapeutic Agents><Nicotinamide-Adenine Dinucleotide Phosphate><Nitrogen><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oncogene K-Ras><Oncogenes><Oncogenic><Operative Procedures><Operative Surgical Procedures><Outcome><Oxidation-Reduction><Oxidative Stress><Oxidative Stress Induction><Pancreas><Pancreas Cancer><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Cancer><Pancreatic Tumor><Pathway interactions><Patient Selection><Patients><Pharmaceutical Preparations><Phenotype><Phosphotransferase Gene><Phosphotransferases><Physiological Homeostasis><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Predisposition><Production><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><Q Levoglutamide><Q. Levoglutamide><RAFB1><RASK2><Redox><Regulation><Reporting><Resected><Role><STK11><STK11 gene><Sampling><Serine><Serine Aldolase><Serine Hydroxymethylase><Serine Hydroxymethyltransferase><Serine Transhydroxymethylase><Signal Transduction><Signal Transduction Systems><Signaling><Sodium Chloride><Source><Stratification><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><Susceptibility><TGF-alpha Receptor><Testing><Therapeutic><Threonine Aldolase><Tissue Growth><Tissues><Transforming Genes><Transforming Growth Factor alpha Receptor><Transgenic Mice><Transphosphorylases><Triphosphopyridine Nucleotide><Tumor Suppressor Proteins><Tumor-Specific Treatment Agents><Up-Regulation><Upregulation><Urogastrone Receptor><Work><amino acid metabolism><anti-cancer drug><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><balance><balance function><biological signal transduction><branched amino acids><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer cell metabolism><cancer metabolism><cancer progression><cancer sub-types><cancer subtypes><chemotherapy><clinical relevance><clinically relevant><driver lesion><driver mutation><drug/agent><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><experience><experiment><experimental research><experimental study><experiments><expression subtypes><genome mutation><in vivo><in vivo Model><insight><interventional strategy><kininogenin><liver kinase B1><lung cancer><lung cancer cell><lung tumorigenesis><metabolic abnormality assessment><metabolome><metabonome><methyl group><mitochondrial><molecular sub-types><molecular subsets><molecular subtypes><mouse model><murine model><mutant><necrocytosis><neoplasm progression><neoplastic progression><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oncogenic KRAS><ontogeny><oxidation reduction reaction><pancreatic cancer model><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor model><pathway><pharmacologic><precision medicine><precision-based medicine><predict clinical outcome><proto-oncogene protein c-erbB-1><salt><social role><subcutaneous><subdermal><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><therapeutically effective><therapy responders><translational opportunities><translational potential><treatment responders><treatment strategy><tumor><tumor cell metabolism><tumor growth><tumor metabolism><tumor progression><tumor suppressor><tumorigenesis in the lung><uptake><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><v-raf Murine Sarcoma Viral Oncogene Homolog B1>