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.

Cancer stem cells (CSCs) are a subpopulation of cancer cells possessing stemness characteristics that are closely associated with tumor proliferation, recurrence and resistance to therapy. Recent studies have shown that different cytoskeletal components and remodeling processes have a profound impact on the behavior of CSCs. In this review, we outline the different cytoskeletal components regulating the properties of CSCs and discuss current and ongoing therapeutic strategies targeting the cytoskeleton. Given the many challenges currently faced in targeted cancer therapy, a deeper comprehension of the molecular events involved in the interaction of the cytoskeleton and CSCs will help us identify more effective therapeutic strategies to eliminate CSCs and ultimately improve patient survival.