Targeting stem-like cells and their niche in pancreatic cancer

Sloan-Kettering Inst Can Research, New York NY

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Abstract

PROJECT SUMMARY 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 advanced 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- differentiation of cancer stem-like cells is an attractive strategy: By homogenizing cancer cell phenotypes within tumors, such therapies may suppress tumor progression and lead to improved responses to conventional therapies. 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 highly plastic basal cells express Slc4a11+, whereas niche cells are marked by Porcupine and DLL1. Hypothesis: Disrupting CSC and niche cells can translate into novel therapeutic strategies for PDAC patients. We propose to identify mechanisms that drive basal niche cell states and to explore the potential of Wnt inhibitors in PDAC therapy. These studies have the potential to translate into new PDAC therapies. Aim 1. Interrogate function of stem-like PDAC cells. We will profile Slc4a11+ 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 Slc4a11+ cells in genetically engineered mouse PDAC tumors. Results will reveal phenotypic shifts in PDAC cell populations, 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 the Porcupine+ niche cell state. We will use a Porcupine reporter allele to ablate these cells in PDAC to evaluate their role in tumor progression, 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 candidate drivers of the basal cell state in PDAC. We will interrogate SOX11, NRARP, and DLL1 alone and in combination with the MEK + HSP90 inhibitor combination, KRAS inhibitors, and chemotherapy agents. These therapies will be tested in orthotopic mouse and patient-derived xenograft models of PDAC. These efforts will test the therapeutic potential of basal state drivers in PDAC, which may sensitize pancreatic tumors to chemotherapy.