The PDAC Extracellular Matrix: A Review of the ECM Protein Composition, Tumor Cell Interaction, and Therapeutic Strategies

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is notorious for a dense fibrotic stroma that is interlaced with a collagen-based extracellular matrix (ECM) that plays an important role in tumor biology. Traditionally thought to only provide a physical barrier from host responses and systemic chemotherapy, new studies have demonstrated that the ECM maintains biomechanical and biochemical properties of the tumor microenvironment (TME) and restrains tumor growth. Recent studies have shown that the ECM augments tumor stiffness, interstitial fluid pressure, cell-to-cell junctions, and microvascularity using a mix of biomechanical and biochemical signals to influence tumor fate for better or worse. In addition, PDAC tumors have been shown to use ECM-derived peptide fragments as a nutrient source in nutrient-poor conditions. While collagens are the most abundant proteins found in the ECM, several studies have identified growth factors, integrins, glycoproteins, and proteoglycans in the ECM. This review focuses on the dichotomous nature of the PDAC ECM, the types of collagens and other proteins found in the ECM, and therapeutic strategies targeting the PDAC ECM.

Keywords: cancer; extracellular matrix; pancreatic ductal adenocarcinoma; proteome; tumor microenvironment.

Figure 1

The dichotomous role of the stroma and common interactions between PDAC tumor cells, the ECM, and CAFs. The stroma’s ECM plays both a tumor promoting role (left) and a tumor suppressive role (right). Tumor promoting roles may include integrin, TGFβ/SMAD, and DDR-1 signaling, as well as providing nutrition via collagen fragments. Tumor suppressive roles may include providing a barrier to metastases and increasing immune response. The ECM (middle) is deposited by CAFs and modulated by MMP, LOX, TG2, HA, and others. CAF, cancer associated fibroblasts; TGF- beta, transforming growth factor beta; HA, hyaluronan; FN-1, fibronectin 1; VN, vitronectin; DDR-1, discoidin receptor 1; PYK2, FAK-related protein tyrosine kinase; FAK, focal adhesion kinase; TG2, tissue transglutimase; LOX, lysyl oxidase.