Date Published: July 10, 2017
Publisher: Public Library of Science
Author(s): Asma Begum, Theodore Ewachiw, Clinton Jung, Ally Huang, K. Jessica Norberg, Luigi Marchionni, Ross McMillan, Vesselin Penchev, N. V. Rajeshkumar, Anirban Maitra, Laura Wood, Chenguang Wang, Christopher Wolfgang, Ana DeJesus-Acosta, Daniel Laheru, Irina M. Shapiro, Mahesh Padval, Jonathan A. Pachter, David T. Weaver, Zeshaan A. Rasheed, William Matsui, Surinder K. Batra.
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.
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 . Despite the approval of new agents, survival rates remain low, and fewer than 5% of patients are alive 5 years after diagnosis . Disease recurrence following surgical resection and metastatic dissemination drives poor outcomes, and tumor initiating cells (TICs) or cancer stem cells (CSCs) have been implicated in both processes [2–7]. The factors regulating CSCs are not fully understood, but the stem cell niche composed of non-stem cells, extracellular matrix (ECM) proteins, and specific signaling molecules maintains the functional properties of normal self-renewing stem cells [8–10]. In PDAC, the tumor microenvironment (TME) is dramatically altered by the densely fibrotic desmoplastic reaction [11–14], and several ECM proteins, including collagen, fibronectin, and laminin, are highly overexpressed . Each of these ECM molecules has been found to promote the growth and invasion of PDAC cells [15–19], and we examined their impact on CSCs.
Cancer stem cells maintain long-term tumor initiating potential and promote metastatic progression in many diseases . These properties suggest that the inhibition of CSCs can improve clinical outcomes, and in normal tissues and organs, stem cells are dependent on cell-extrinsic niche factors. Striking changes occur within the TME suggesting that specific extrinsic factors similarly impact CSCs. In pancreatic carcinoma, the TME is dominated by the desmoplastic reaction, and we found that type I collagen enhances tumor-initiating potential, self-renewal, and cellular migration and invasion through β1integrin and FAK signaling.