The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.

Keywords: cancer stem cells; chemotherapy resistance; extracellular matrix; metastasis; pancreatic ductal adenocarcinoma.

Figure 1

Signaling pathways that are associated with matrix stiffness. Matrix stiffness activates a large number of mechano-responsive signaling pathways in different cells through integrins, ion channels, and other transmembrane proteins. Pathways such as PI3K, RhoA-ROCK, and YAP/TAZ play major roles in this conduction. The central players in these signaling pathways can be connected to other molecules to eventually transform the changes in the ECM into related biological changes and phenotypes.