Abstract
Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration in vitro and tumor initiation, growth, and metastasis in vivo in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth in vitro and in vivo. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) leads to an estimated 40,000 deaths annually and is the fourth leading cause of cancer related deaths in the United States [1]
We found that aldehyde dehydrogenase (ALDH)+ cells are enriched at the interface between tumor cells and the desmosplastic reaction, suggesting that cancer stem cells (CSCs) interact with the tumor microenvironment (TME) [6]
These properties suggest that the inhibition of CSCs can improve clinical outcomes, and in normal tissues and organs, stem cells are dependent on cellextrinsic niche factors
Summary
Pancreatic ductal adenocarcinoma (PDAC) leads to an estimated 40,000 deaths annually and is the fourth leading cause of cancer related deaths in the United States [1]. In PDAC, the tumor microenvironment (TME) is dramatically altered by the densely fibrotic desmoplastic reaction [11,12,13,14], and several ECM proteins, including collagen, fibronectin, and laminin, are highly overexpressed [14]. Each of these ECM molecules has been found to promote the growth and invasion of PDAC cells [15,16,17,18,19], and we examined their impact on CSCs
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