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.

The Extracellular Matrix: Its Composition, Function, Remodeling, and Role in Tumorigenesis

“…ECM stiffness impacts the adhesion of cells, movement of cells, and response to therapy [ 407 , 408 , 409 , 410 , 411 ]. Increased matrix stiffness within tumors is linked to less responsive tumors and drug resistance ( Figure 5 ) [ 388 , 412 , 413 ]. Generally, stiffer ECMs are found surrounding tumors compared to ECMs in normal tissues [ 410 , 414 , 415 , 416 , 417 , 418 , 419 , 420 ].…”

Application of aptamer functionalized nanomaterials in targeting therapeutics of typical tumors

“…Abnormal expression of extracellular matrix in tumor stroma forms a dense physical barrier, which leads to extravasation and insufficient infiltration of nanotherapy ( Wang et al, 2022a ). Huang et al modified lipid nanocarriers (LPNs) with J10 aptamer and loaded gemcitabine on LPNs, and synthesized nanoparticles J10-GEM-LNPS with active targeting to tumor cells ( Huang et al, 2021 ).…”

The Extracellular Matrix: Composition, Function, Remodeling and Its Role in Tumorigenesis<i></i>

“…ECM stiffness impacts adhesion of cells, movement of cells, and response to therapy [430][431][432][433][434]. Increased matrix stiffness within tumors is linked to less responsive tumors and drug resistance (Figure 4) [408,435,436]. Generally, stiffer ECMs are found surrounding tumors compared to ECM in normal tissues [433,[437][438][439][440][441][442][443].…”