Abstract 2446: Targeting pancreatic cancer stem cells via the tumor microenvironment

Abstract

Abstract Pancreatic adenocarcinoma is a highly aggressive disease with a propensity for metastasis early in its course. Pancreatic cancer stem cells (CSCs) have been thought to play a key role in this process. We previously found that pancreatic CSCs express increased levels of aldehyde dehydrogenase (ALDH) and at the time of diagnosis the presence of ALDH+ cells in primary tumors is associated with worse overall survival. The development of CSC-targeting strategies have largely focused on intrinsic signaling pathways, but normal stem cells are primarily regulated by the extracellular stem cell niche that consists of non-malignant cells and specific extracellular matrix (ECM) proteins. The densely fibrotic desmoplastic reaction (DR) is a common feature of pancreatic tumors, thus we examined the role of the ECM on pancreatic CSCs. We initially studied the distribution of ALDH+ cells in primary pancreatic tumors by immunohistochemistry and found that they were more frequently located at the invasive edge of tumors adjacent to the DR compared to the rest of the tumor (<5% of all cells). These findings suggested that the DR influences CSC properties and we cultured pancreatic cancer cell lines and primary tumors in the presence of type I collagen since it is the major ECM component of the DR and has been shown to increase the proliferation and survival of pancreatic tumor cells. Compared to cells cultured under standard conditions, type I collagen increased the proportion of ALDH+ cells, clonogenic growth and migratory potential in vitro. To determine if collagen provides a selective advantage to ALDH+ cells or induces ALDHneg cells to acquire a CSC phenotype, we studied isolated ALDH+ cells and found that they maintained their CSC phenotype to a higher degree (2-3 fold) in the presence of type I collagen compared to those cultured on plastic or matrigel. In contrast, ALDHneg cells cultured on collagen remained phenotypically similar to those cultured on plastic or matrigel. We also found that type I collagen induced further mesenchymal properties in ALDH+ cells as evidenced by decreased expression of E-cadherin and greater migratory potential. Furthermore, we found that expression of α2β1 integrin, a specific receptor for type I collagen, was restricted to ALDH+ cells. In order to target the interaction between type I collagen and pancreatic CSCs we studied focal adhesion kinase (FAK), a major component of integrin signal transduction, and found that ALDH+ cells expressed higher levels of activated, phosphorylated FAK compared to the bulk tumor cell population. Finally, we found that pharmacologic inhibition of FAK resulted in the loss of ALDH+ cells, clonogenic growth, and cellular migration. Our data suggest that the interaction between pancreatic CSCs and the DR results in enhanced tumorigenicity and metastatic potential. Furthermore, the disruption of FAK signaling can inhibit pancreatic CSC function and may serve as a novel therapeutic strategy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2446. doi:10.1158/1538-7445.AM2011-2446