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.

Upregulated integrin α11 in the stroma of cutaneous squamous cell carcinoma promotes skin carcinogenesis

“…Substantial evidence has been gathered to demonstrate the relevance of α11β1 signaling in CAFs in distinct solid cancer types, as well as in myofibroblasts during wound healing [reviewed in ( 4 , 11 )]. Here, we report our novel findings on the notable upregulation of integrin α11 expression in the stromal compartment of human and mouse cSCCs, as well as the significant impairment of DMBA/TPA-induced skin tumor growth in mice, accompanied by interesting alterations in the tumor stroma, in the absence of α11 integrin.…”

“…The non-vascular, non-inflammatory stromal cells within the TME are designated cancer-associated fibroblasts (CAFs) (3). Recent single-cell RNA sequencing (scRNA-seq), proteomics and flow cytometry approaches have revealed extraordinary heterogeneity and plasticity among CAFs subpopulations (2)(3)(4). The three major subtypes of CAFs, originally identified in pancreatic adenocarcinoma (PDAC), are myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs) (5,6).…”

“…CAFs are often characterized by the synthesis of ECM proteins, including fibrillar collagens, proteoglycans, matricellular proteins, and ECM-modifying enzymes, contributing to tumor fibrosis (2,7). A current challenge in TME research involves identifying, characterizing, and targeting tumor-promoting CAF subtypes (2)(3)(4).…”

Forces exerted and transduced by cancer‐associated fibroblasts during cancer progression

“…DDR2 has also been shown to control the activation of collagen‐binding integrins. Sydecans, additional non‐integrin receptors, have been reported on CAFs and are often related to TGF‐β signaling (particularly Syndecan‐2), but remain an understudied area of CAF mechanobiology (Zeltz et al., 2022).…”

FNIII14 Peptide-Enriched Membrane Nanocarrier to Disrupt Stromal Barriers through Reversing CAFs for Augmenting Drug Penetration in Tumors

“…Additionally, our previous studies have demonstrated that the crosstalk between CAFs and tumor cells can promote tumor growth and metastasis. , All these functions contribute to tumor growth, invasion, and metastases, which indicate the potential of CAFs’ functions reversing to overcome stromal barriers. Interestingly, integrins, as cell adhesion receptors, have attracted significant attention owing to their roles in desmoplasia and matrix remodeling. , They are heterodimeric transmembrane receptors composed of α and β subunits, the latter of which are verified to be crucial for cell-to-ECM and cell-to-cell interaction. − Specifically, integrin β1 (ITGB1) in TME forms specific receptors for fibronectin, laminin, or collagen. − Also, ITGB1 participates in CAFs self-renewal and their expression of α-smooth muscle actin (α-SMA, ACTA2) and COL1A1, thus regulating the synthesis of ECM. − These findings indicate the significant importance of ITGB1 as a target to regulate the CAFs’ functions for remodeling ECM.…”