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.

Mesenchymal stem/stromal cells (MSCs) have been isolated from various tissues and utilized for an expanding number of therapies. The developmental pathways involved in producing MSCs, and the phenotypic precursor/progenitor cells that give rise to human MSCs remain poorly defined. Human embryonic stem cells (hESCs) have the capability to generate functional hemato-endothelial cells and other mesoderm lineage cells. hESC-derived CD73 + cells have been isolated and found to have similar phenotypic and functional characteristics as adult MSCs. Here we demonstrate hESC-derived CD34 + CD73 -cells can serve as MSC progenitor cells with the ability to differentiate into adipocytes, osteoblasts and chondrocytes. Additionally, gene array analysis of hESC-derived MSCs show substantially different gene expression compared to bone marrow (BM) -derived MSCs, especially with increased expression of pluripotent and multipotent stem cell and endothelial cell-associated genes. The isolation of functional MSCs from hESC-derived CD34 + CD73 -cells provides improved understanding of MSC development and utilization of pluripotent stem cells to produce MSCs suited for novel regenerative therapies.

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Cancer stem cells (CSCs) have been identified in an ever-increasing number of human malignancies based on the ability to recapitulate tumors in the ectopic setting and maintain long-term tumorigenic potential. In pancreatic adenocarcinoma, CSCs may also display additional properties, such as relative drug resistance and enhanced invasive and migratory potential that implicate a role in disease pathogenesis spanning initial tumor formation to metastatic disease progression. Importantly, these findings also suggest that the development of novel therapeutic strategies capable of inhibiting or eliminating CSCs will improve clinical outcomes. Preclinical studies have already described a wide array of potential targeting approaches that target CSC-specific surface antigens and cellular pathways involved in cell survival, adhesion, self-renewal and differentiation. Furthermore, progress in this area should continue to move forward as the unique biology of CSCs is better understood. All preclinical studies to date have focused on targeting specific and phenotypically defined CSCs, but multiple cell populations with the ability to form tumors and self-renew have been identified in pancreatic carcinoma. Since the clinical efficacy of CSC-directed therapies will depend on the inhibition of all sources of tumor self-renewal, better understanding how specific CSC populations are related to one another and whether each possesses specific functional properties will be critical. In this review, we will discuss the potential relationships between different pancreatic CSC populations and strategies to identify novel targeting approaches.