Project Summary The Cancer Stem Cell (CSC) theory, which was first proposed more than four decades ago, states that a small population of cancer cells possess the characteristics associated with normal stem cells such as the capacities for self-renewal and multi-lineage differentiation, is the primary driver of tumor heterogeneity, progression, and resistance. However, there have been on-going controversies regarding the origins, identities and functions of CSCs, in large part due to the lack of vigorous and physiological approaches to specifically identify, track, and target the rare CSC population in intact tumors. To fill this gap, we have developed a new inducible genetically engineered mouse model (GEMM) of Pancreatic ductal adenocarcinoma (PDAC), which enable us to conduct in vivo lineage tracing, ablation, as well as ex vivo analysis of the CSC niches from autochthonous PDAC tumors. Using this powerful new system, our proposal will examine (1) the dynamics of the CSC niches during PDAC progression and relapse, (2) the performance of previously described putative PDAC “CSC” markers, and (3) the functional significance of the CSC niches to PDAC invasion, metastasis and chemo-resistance.

Public Health Relevance Statement The Cancer Stem Cell (CSC) theory states that a rare population of cancer cells with characteristics of normal stem cells is the primary driver of tumor invasion, metastasis and drug resistance, and therefore represent the key targets for cancer eradication. However, there have been on-going controversies regarding the origins, identities and functions of CSCs, in large part due to the lack of vigorous and physiological approaches to specifically identify, track, and target the rare CSC population in intact tumors. In this proposal, we will apply a new inducible genetically engineered mouse model (GEMM) of Pancreatic ductal adenocarcinoma (PDAC) to (1) examine the dynamics of the CSC niches during the natural course of PDAC malignant progression and relapse, (2) assess the performance of previously described putative PDAC “CSC” markers, and (3) establish the functional significance of the CSC niches to PDAC invasion, metastasis and chemo-resistance.