The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma

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.

The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship

“…For example, the migration of PANC-1 and UlaPaCa cells along collagen I gradients is mediated by the activation of the focal adhesion kinase (FAK) pathway by collagen I-integrin signaling [ 59 ]. In PDAC, collagen I-mediated activation of the FAK pathway also increases colony formation, clonogenic growth, and self-renewal [ 60 , 61 ]. Additionally, activation of FAK by collagen I may regulate epithelial to mesenchymal transition (EMT).…”

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…Modulation of the downstream mediators and interacting partners of Src represents another potentially viable therapeutic approach that is increasingly being investigated ( Table 2). Inhibition of FAK decreased PDAC cell growth and migration in vitro [191,192], and limited pancreatic tumour progression in vivo, doubling the survival in the p48-Cre;LSL-KrasG12D; Trp53flox/+ (KPC) mouse model of PDAC [25,193,194]. FAK inhibitor VS-4718 treatment further reduced tumour fibrosis and numbers of infiltrating immunosuppressive populations of myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and regulatory T-cells, sensitising the KPC mouse model to checkpoint immunotherapy [25].…”

Integrated analysis of circular RNA‑associated ceRNA network in pancreatic ductal adenocarcinoma

“…The GO and KEGG enrichment analyses suggest that these DEmRNAs have a significant effect on tumor-associated biological functions. Among the 12 total pathways, 'focal adhesion', 'ECM-receptor interaction', 'microRNAs in cancer' and 'proteoglycans in cancer' are associated with the progression of PDAC (45)(46)(47)(48). The PPI network was established, including the six hubgenes (THBS1, FN1, TGFB2, ITGA1, ITGA3, and TIMP3), to further identify the key circRNAs participating in the regulatory network.…”