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Principal Investigator: Beatriz Mateo-Victoriano
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $48,974
Funding agency: National Cancer Institute
Project Summary
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths with a 5-year survival
rate of 12%. Over 90% of PDAC is driven by oncogenic KRAS, however inhibitors targeting KRAS have been
unsuccessful in the clinic thus far. Targeting oncogenic vulnerabilities is a key alternative approach. Oncogenic
RAS-generated reactive oxygen species (ROS) drives tumor progression through hyperactivation of proliferative,
anti-apoptotic, and metastatic pathways. However, ROS can also trigger tumor suppressive outcomes through
cellular damage. The nucleotide pool-cleansing 8-oxo-dGTPase MutT Homolog 1 (MTH1) is a critical redox
protective adaptation in RAS-driven tumor cells to overcome tumor-inhibitory ROS mediated consequences.
MTH1 has been shown to prevent oncogene-induced oxidative stress and damage, and maintain high KRAS
oncoprotein expression, associated ROS-driven oncogenic signaling, and tumorigenicity in lung cancer. Given
the importance of MTH1 in KRAS oncogenic biology and the fact that over 90% of PDAC is driven by oncogenic
KRAS, I propose that MTH1 is similarly important in PDAC. In support of this idea, TCGA analysis revealed
MTH1 expression is significantly higher in tumor tissue compared to normal tissue, and high MTH1 significantly
correlates with poor disease-free survival. The Rai lab reported 8-oxodGTPase activity is significantly elevated
in patient PDAC tumor vs. normal tissue. Preliminary data show MTH1 loss reduces tumor burden in a subset of
PKT cohorts, with lower burden associated with both reduced intratumoral EGFR expression and in cytokines
associated with an immunosuppressive tumor microenvironment (TME). When MTH1 is depleted via shRNA in
PDAC cell lines, there is a significant decrease in proliferation associated with decreased total EGFR. Analysis
of human PDAC tumor data through TIMER 2.0 shows intratumoral MTH1 expression significantly correlates
with infiltration of myeloid derived suppressor cells (MDSCs), suggesting high MTH1 expression supports and/or
creates the immunosuppressive TME that make PDAC so difficult to treat. Therefor I hypothesize MTH1 is
important for PDAC tumorigenesis through both tumor cell-intrinsic as well as previously-unappreciated
extrinsic mechanisms. To test this hypothesis, I will use our novel PKT mouse models with systemic and
pancreas-specific MTH1 loss. Experiments proposed in Aim 1 will assess how systemic vs pancreas-specific
MTH1 loss affects in vivo KRAS tumorigenesis; Aim 2 will independently ascertain how MTH1 regulates KRAS-
driven transformation and PDAC chemoresistance. Upon completion of these studies, we will establish novel
mechanisms by which MTH1 regulates tumorigenesis thus filling a gap in the field regarding the link between
MTH1 and KRAS in PDAC. Lastly, these aims have the potential to validate MTH1 as an alternative to targeting
oncogenic KRAS in PDAC patients which has been unsuccessful to date.
Terms: <Active Oxygen><Address><Affect><Animal Experimental Use><Animal Experimentation><Animal Research><Animals><Apoptotic><Area><Biology><Body Tissues><C-K-RAS><COVID-19><CV-19><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Model><Cancer-Promoting Gene><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><Cell Signaling><CellLine><Cells><Cellular Proliferation><Cellular injury><Cessation of life><Chemoresistance><Clinic><Clinical><Coronavirus Infectious Disease 2019><DNA><DNA Damage><DNA Injury><Data><Death><Death Rate><Deoxyribonucleic Acid><Development><Disease><Disease-Free Survival><Disorder><EGF Receptor><EGFR><ERBB Protein><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epithelial Cells><Event-Free Survival><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><GeneHomolog><Genetic Alteration><Genetic Change><Genetic defect><Genomic DNA><Genotype><Germ Lines><HER1><Homolog><Homologous Gene><Homologue><Human><Immune><Immunes><Infiltration><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS driven oncogenesis><KRAS oncogenesis><KRAS(G12D)><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><KRAS2><KRAS2 gene><KRASG12D><Ki-RAS><Link><LoxP-flanked allele><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Modeling><Modern Man><Molecular><Molecular Analysis><Mutation><Myeloid-derived suppressor cells><Normal Cell><Normal Tissue><Normal tissue morphology><Nucleotides><Oncogene K-Ras><Oncogene Products><Oncogene Proteins><Oncogenes><Oncogenesis><Oncogenic><Oncoproteins><Outcome><Oxidation-Reduction><Oxidative Stress><Oxidative Stress Induction><Oxygen Radicals><PDAC cancer cell><PDAC cell><Pancreas><Pancreas Ductal Adenocarcinoma><Pancreatic><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patients><Pattern><Pro-Oxidants><Proliferating><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><RAS driven tumor><RASK2><Radiation><Reactive Oxygen Species><Redox><Reporting><Research><Resistance><Role><Signal Transduction><Signal Transduction Systems><Signaling><Standard Model><Strains Cell Lines><Stress><Survival Rate><TCGA><TGF-alpha Receptor><Testing><The Cancer Genome Atlas><Therapeutic><Therapeutic Intervention><Time><Tissues><Transforming Genes><Transforming Growth Factor alpha Receptor><Tumor Burden><Tumor Cell><Tumor Load><Tumor Promotion><Tumor Tissue><Tumorigenicity><United States><Urogastrone Receptor><Validation><animal experimentations><biological signal transduction><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer microenvironment><cancer progression><cell damage><cell injury><cellular damage><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><cohort><conditional knock-out><conditional knockout><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cultured cell line><cytokine><damage to cells><developmental><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><experiment><experimental research><experimental study><experiments><flow cytophotometry><floxed><floxed allele><gDNA><genome mutation><immune microenvironment><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive tumor microenvironment><in vitro Model><in vivo><inhibitor><injury to cells><intervention therapy><knock-out animal><knockout animal><lung cancer><malignancy><metabolic profile><mortality rate><mortality ratio><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oncogenic KRAS><overexpress><overexpression><oxidation reduction reaction><oxidative damage><oxidative injury><pancreatic ductal adenocarcinoma cell><paracrine><pathway><pharmacologic><prevent><preventing><proto-oncogene protein c-erbB-1><repair><repaired><resistant><response><sample archive><scRNA-seq><senescence><senescent><shRNA><short hairpin RNA><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small hairpin RNA><small molecule><social role><standard of care><suppressive myeloid cells><therapeutically effective><tool><tumor><tumor immune microenvironment><tumor microenvironment><tumor progression><tumor-immune system interactions><tumorigenesis><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><validations>