Integrin α11β1 in tumor fibrosis: more than just another cancer-associated fibroblast biomarker?

Abstract

There is currently an increased interest in understanding the role of the tumor microenvironment (TME) in tumor growth and progression. In this context the role of integrins in cancer-associated fibroblasts (CAFs) will need to be carefully re-evaluated. Fibroblast-derived cells are not only in the focus in tumors, but also in tissue fibrosis as well as in inflammatory conditions. The recent transcriptional profiling of what has been called "the pan-fibroblast cell lineage" in mouse and human tissues has identified novel transcriptional biomarker mRNAs encoding the secreted ECM proteins dermatopontin and collagen XV as well as the phosphatidylinositol-anchored membrane protein Pi16. Some of the genes identified in these fibroblasts scRNA-seq datasets will be useful for rigorous comparative characterizations of fibroblast-derived cell subpopulations. At the same time, it will be a challenge in the coming years to validate these transcriptional mRNA datasets at the protein-(expression) and at tissue-(distribution) levels and to find useful protein biomarker reagents that will facilitate fibroblast profiling at the cell level. In the current review we will focus on the role of the collagen-binding integrin α11β1 in CAFs, summarizing our own work as well as published datasets with information on α11 mRNA expression in selected tumors. Our experimental data suggest that α11β1 is more than just another biomarker and that it as a functional collagen receptor in the TME is playing a central role in regulating collagen assembly and matrix remodeling, which in turn impact tumor growth and metastasis.

Keywords: Cancer therapy; Cancer-associated fibroblast; Fibrosis; Integrin; Tumor microenvironment.

Fig. 1

Cancer-associated fibroblasts. Cancer-associated fibroblasts (CAFs) are activated fibroblasts, which are called myofibroblasts when they harbor myofibroblastic features such as α-SMA expression. They are mainly derived from resident fibroblasts but can also be contributed from stellate cells in the context of liver and pancreatic cancer (as well as other cell types such as adipocytes and endothelial cells). Tumor cells by secreting soluble factors could initiate fibroblast activation and myofibroblast differentiation. Activated fibroblasts can differentiate into myofibroblasts and this process has been shown to be reversible in a pancreatic cancer model. Myofibroblastic CAFs are mainly involved in the deposition and reorganization of the extracellular matrix (ECM) in the tumor stroma to induce stiffness and linearized matrix fibrils, which in turn promote tumor growth, cell invasion and metastasis. A stiff ECM can also act as a barrier to prevent therapeutic agent delivery to the tumor and prevent access of immune cells. However, in a different tissue context, CAF-mediated organized ECM can restrain tumor growth and invasion. In parallel of myofibroblast activity, activated fibroblasts secrete different soluble factors (growth factors (GF), cytokines) that can promote tumor growth and invasion, immune suppression by recruiting tumor-associated regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and chemoresistance, e.g., via the compensation of signaling pathways and drug efflux

Fig. 2

Integrin α11 expression in CAF heterogeneity. Main cancer-associated fibroblast (CAF) subpopulations of lung adenocarcinoma (LUAD), pancreatic ductal adenocarcinoma (PDAC) and breast cancer are represented based on scRNA-seq dataset from Kim et al., , Dominguez et al., and Bartoschek et al., , respectively. For each subset of CAFs, the name is underlined and some specific markers are given. In LUAD, integrin α11 (ITGA11) mRNA is mainly observed in the myofibroblast cluster and in few cells of the COL14A1⁺ matrix fibroblast subset. In the mouse model of PDAC, integrin α11 (Itga11) mRNA is found in the Lrrc15⁺ c2 CAF subpopulation, with myofibroblastic features, which derived from the c1 CAF subset, which itself evolved from the c4 tissue fibroblast population, driven by TGF-β signaling. In parallel, IL-1 drive the evolution of c3 fibroblast subpopulation to c0 and then to the c8 inflammatory CAF subset. In the mouse breast cancer model, integrin α11 (Itga11) mRNA is mostly observed in the matrix CAF subpopulation, thought to derive from resident fibroblasts. Few cells from the “developmental CAF” subset, suggested to be malignant cells that have undergone epithelial-to-mesenchymal transition (EMT), are Itga11⁺