Abstract IA6: The role of pancreatic cancer stem cells in metastasis.

Abstract

Pancreatic adenocarcinoma is a highly aggressive disease with a propensity for metastasis. The process of metastasis requires that cells be able to migrate out of the primary tumor and give rise to a histologically similar tumor in a distant organ. Recent studies have implicated pancreatic cancer stem cells (CSCs), functionally defined by their ability to initiate tumor formation, in metastasis. We, along with others, have identified invasive subsets of pancreatic CSCs based on cell surface antigen (CD44 + CD24 + c-Met + and CD133 + CXCR4 + ) expression and aldehyde dehydrogenase (ALDH) activity. The presence of ALDH-expressing CSCs in patients’ primary pancreatic tumors have been associated with worse clinical prognosis and implicated in metastasis formation. Thus, revealing the clinical significance of CSCs and underscoring the importance of developing novel CSC-targeting agents. Development of these agents will require better understanding the extrinsic factors and intrinsic signaling pathways that regulate specific pancreatic CSC functions (e.g., invasion, self-renewal). We have begun to study extrinsic factors that regulate pancreatic CSC function. Compared to pancreatic cancer cells cultured under standard conditions, cells cultured in the presence of pancreatic cancer-associated fibroblasts (CAFs) or type I collagen [a major constituent of the extracellular matrix (ECM)], developed a higher proportion of ALDH + cells with concomitant increases in clonogenic growth and migration. The effect of type I collagen is specific to ALDH + cells, since isolated ALDH + cells maintained their CSC phenotype to a higher degree in the presence of type I collagen compared to those cultured on plastic or Matrigel, whereas type I collagen had no effect on ALDH neg cells. These studies suggest that ALDH + CSCs have intrinsic properties that make them more susceptible to the effects of CAFs and ECM proteins. Given their importance in ECM-mediated signaling, we studied integrin and focal adhesion kinase (FAK) in pancreatic CSCs. Compared to the bulk tumor cell population, we discovered that protein expression of the α2β1 integrin heterodimer and phospho-tyrosine-397 FAK (the activated form of FAK) is enriched in ALDH + cells. Pharmacologic and genetic targeting of these proteins leads to a loss of pancreatic CSC function. This and other novel strategies that target pancreatic CSCs offer new promises for the development of effective therapies for patients with pancreatic adenocarcinoma. Citation Format: Zeshaan A. Rasheed. The role of pancreatic cancer stem cells in metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr IA6.