Less than 8% of pancreatic ductal adenocarcinoma (PDAC) patients are alive 5 years after diagnosis. PDAC is typically diagnosed at an advanced stage, limiting treatment options. Chemotherapies are the mainstay for ad- vanced PDAC, though they produce incomplete responses. Thus, development of novel therapies for PDAC patients is urgently needed. A possible explanation for failure of standard chemotherapies in PDAC is cellular phenotypic heterogeneity within tumors. Heterogeneity may enable subpopulations of cells to survive therapy and repopulate the tumor. Cancer stem-like cells (CSCs) have been described in multiple solid tumor types. CSCs have robust proliferative potential and are typically resistant to cancer therapies. Elimination or re-differ- entiation of cancer stem-like cells is an attractive strategy: By homogenizing cancer cell phenotypes within tu- mors, such therapies may suppress tumor progression and lead to improved responses to conventional thera- pies. Our pilot data suggest that secreted Wnt ligands produced by one cancer cell subpopulation drive a stem- like state in another cancer cell subpopulation, in essence forming a specialized microenvironment, or niche, within pancreatic tumors that maintains CSCs. We found that CSCs express Wnt target gene Lgr5, whereas niche cells are marked by Porcupine, an enzyme that post-translationally modifies Wnt. Hypothesis: Disrupting CSC and niche cells can translate into novel therapeutic strategies for PDAC patients. We propose to identify mechanisms that drive Lgr5+ CSC and Porcupine+ niche cell states and to explore the potential of Wnt inhibi- tors in PDAC therapy. These studies have the potential to translate into new PDAC therapies.
Aim 1. Interro- gate function of Lgr5+ stem-like PDAC cells. We will profile Lgr5+ pancreatic cancer cells and evaluate ability to functionally contribute to PDAC progression, metastasis, and resistance to chemotherapy. We will perform lineage-tracing and -ablation, and gene expression and proteomic profiling of Lgr5+ cells in genetically engi- neered mouse PDAC tumors. Results will determine whether Lgr5+ cells are CSCs in established tumors and inform their molecular characteristics, which may provide added means to target these cells.
Aim 2. Elucidate biology of Porcupine+ PDAC niche cells. We will identify molecular mechanisms that drive Porcupine+ niche cell state. We will use Porcupine reporter allele to ablate these cells in PDAC to evaluate role in tumor progres- sion, and isolate niche cells for proteomic and gene expression profiling. Results will provide insights into role of Porcupine+ cells in PDAC progression and how to target them.
Aim 3. Therapeutically target Wnt signaling in PDAC. We will target Wnt signaling by using small molecule inhibitors of Porcupine as single agents and in combination with chemotherapy. To improve delivery of these drugs into desmoplastic PDAC tumors, we will complex them with cyclodextrin carrier molecules. These therapies will be tested in orthotopic mouse and pa- tient-derived xenograft models of PDAC in RNF43 wild-type and mutant PDAC. These efforts will test thera- peutic potential of Wnt inhibitors in PDAC, which may sensitize pancreatic tumors to chemotherapy.

Public Health Relevance

A possible explanation for failure of standard chemotherapies in pancreatic ductal adenocarcinoma (PDAC) is cellular phenotypic heterogeneity within tumors, which may enable subpopulations of cells to survive therapy and repopulate the tumor. Elimination or re-differentiation of cancer stem-like cells (CSCs) is an attractive strat- egy-- by homogenizing cancer cell phenotypes within tumors, such therapies may suppress tumor progression and lead to improved response to conventional therapies. We hypothesize that disrupting CSC and niche cells can translate into novel therapeutic strategies for PDAC patients, and therefore we propose to identify mecha- nisms that drive the Wnt target gene Lgr5 (expressed by CSCs) and Porcupine+ niche cell states and to ex- plore the therapeutic potential of Wnt inhibitors in PDAC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA244911-02
Application #
10083206
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Ault, Grace S
Project Start
2020-01-08
Project End
2024-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065