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Principal Investigator: Kenneth L Pitter
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $393,750
Funding agency: NIH Office of the Director
PROJECT SUMMARY/ABSTRACT
Individual cells within a given cancer type are capable of expressing a diversity of phenotypic states resulting
from an underlying heterogeneity of genetic, epigenetic, transcriptomic, and molecular features. How this
diversity evolves and influences therapeutic response is an essential question in cancer biology. One emerging
mechanism of developing such heterogeneity is the evolution of microenvironmental niches within tumors that
support a cancer stem cell (CSC) state. CSCs are defined by their functional capabilities such as long-term self-
renewal, the capacity to give rise to a range of differentiated cell types, and enhanced tumor-forming ability.
They are also believed to drive resistance to anti-tumor therapies, such as radiation therapy. Pancreatic ductal
adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year overall survival of <10% and a dire need for novel
therapeutic strategies. Radiation is an integral part of PDAC therapy, however not all cancer cells respond.
Identifying mechanisms of radioresistance would transform the clinical management of PDAC. Using pancreatic
tumor models, our preliminary results suggest that secreted Wnt ligands produced by one cancer cell subset
drive a Lgr5+ stem-like state in another cancer cell subset, in essence forming a supportive niche that promotes
stemness within pancreatic tumors. In this proposal, I will test the central hypothesis that Wnt-driven cellular
phenotypic heterogeneity and stemness promote radiotherapy resistance in pancreatic adenocarcinoma. I will
examine the role of pancreatic tumor cell subpopulations in radiation resistance, including the Lgr5+ cells (Aim
1) and the Wnt producing niche (Aim 2). Under Aim 1, I will characterize the cancer stem cell properties of
Lgr5+ cells in pancreatic cancer, their relative resistance to radiation therapy, and their role in tumor
repopulation. These results will determine whether Lgr5+ cells are CSCs and drivers of radioresistance in
established tumors and inform their molecular characteristics, which may provide added means to target these
cells. Under Aim 2, I will investigate the targeting of the Wnt-producing niche in combination with radiation.
Specifically, I will use genetic or pharmacologic perturbation of the Wnt pathway in combination with radiation
and assay tumor response and animal survival. These efforts will test the therapeutic potential of Wnt inhibitors
as radiosensitizers in PDAC. Collectively, this work will facilitate basic mechanistic insights into both cellular
heterogeneity and radioresistance, with the ultimate goal of translating these discoveries and developing
improved treatment strategies for PDAC patients.
Terms: <21+ years old><Ablation><Acyltransferase><Address><Adult><Adult Human><Animal Experimental Use><Animal Experimentation><Animal Research><Animals><Assay><Award><Bioassay><Biochemical><Biological><Biological Assay><Cancer Biology><Cancers><Career Mobility><Cell Body><Cell Differentiation><Cell Differentiation process><Cells><Characteristics><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinic><Clinical><Clinical Management><Colorectal Adenocarcinoma><Core Facility><Data><EC 2.3><Eligibility><Eligibility Determination><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evolution><Faculty><GEM model><GEMM model><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genetic><Genetic Heterogeneity><Genetically Engineered Mouse><Goals><HG38><Heterogeneity><Human><Immune Cell Activation><Immune mediated therapy><Immunocompetent><Immunologically Directed Therapy><Immunotherapy><Individual><Institution><Intratumoral heterogeneity><LGR5><LGR5 gene><Laboratories><Laboratory Research><Large Bowel Adenocarcinoma><Large Intestine Adenocarcinoma><Letters><Ligands><Localized Disease><Lung Adenocarcinoma><MSKCC><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Memorial Sloan-Kettering Cancer Center><Mentors><Methods><Mice><Mice Mammals><Minority><Mitogenesis><Modern Man><Molecular><Murine><Mus><Operative Procedures><Operative Surgical Procedures><PDA model><PDAC Model><PDAC cancer cell><PDAC cell><Pancreas><Pancreas Adenocarcinoma><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Injury><Pancreatic Trauma><Pancreatic Tumor><Pathway interactions><Patients><Phenotype><Population><Porcupines><Position><Positioning Attribute><Positive Control of Cell Proliferation><Postdoc><Postdoctoral Fellow><Productivity><Prognosis><Property><Protocol Screening><Radiation><Radiation Sensitizers><Radiation therapy><Radiation-Sensitizing Agents><Radiation-Sensitizing Drugs><Radioresistance><Radiosensitization><Radiosensitizing Agents><Radiosensitizing Drugs><Radiotherapeutics><Radiotherapy><Radiotherapy sensitizer><Research><Research Associate><Research Resources><Resistance><Resources><Role><Secure><Shapes><Stem Cell like><Stimulation of Cell Proliferation><Surgical><Surgical Interventions><Surgical Procedure><Testing><Therapeutic><Training><Transcript Expression Analyses><Transcript Expression Analysis><Translating><Translations><WNT Signaling Pathway><WNT signaling><Work><adulthood><analyze gene expression><animal experimentations><biologic><cancer cell><cancer heterogeneity><cancer microenvironment><cancer progenitor><cancer progenitor cells><cancer stem cell><cancer type><career advancement><career transition><cell type><cellular differentiation><chemo-/radio-sensitization><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><conventional therapy><conventional treatment><disease control><disorder control><epigenetically><experience><gene expression analysis><gene expression assay><genetically engineered mouse model><genetically engineered murine model><graduate student><heterogeneity in tumors><immune activation><immune competent><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><inhibitor><insight><interest><intra-tumoral heterogeneity><intratumor heterogeneity><malignancy><malignant progenitor><malignant stem cell><member><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><palmitoylation><pancreatic cancer cells><pancreatic cancer model><pancreatic ductal adenocarcinoma cell><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><pancreatic tumor model><pathway><pharmacologic><post-doc><post-doctoral><post-doctoral trainee><professor><programs><radiation or chemotherapy><radiation resistance><radiation sensitization><radiation treatment><radio resistance><radio-/chemo-sensitization><radio-sensitization><radiosensitizer><radiotherapy sensitization><research associates><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><self-renew><self-renewal><small molecule><social role><stem><stem cell characteristics><stemness><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tenure process><tenure track><therapeutic evaluation><therapeutic resistance><therapeutic response><therapeutic target><therapeutic testing><therapy resistant><therapy response><transcriptional profiling><transcriptomics><translation><treatment resistance><treatment response><treatment responsiveness><treatment strategy><treatment with radiation><tumor><tumor growth><tumor heterogeneity><tumor microenvironment>