Collagen VI sustains cell stemness and chemotherapy resistance in glioblastoma

Abstract

Microenvironmental factors are known fundamental regulators of the phenotype and aggressiveness of glioblastoma (GBM), the most lethal brain tumor, characterized by fast progression and marked resistance to treatments. In this context, the extracellular matrix (ECM) is known to heavily influence the behavior of cancer cells from several origins, contributing to stem cell niches, influencing tumor invasiveness and response to chemotherapy, mediating survival signaling cascades, and modulating inflammatory cell recruitment. Here, we show that collagen VI (COL6), an ECM protein widely expressed in both normal and pathological tissues, has a distinctive distribution within the GBM mass, strongly correlated with the most aggressive and phenotypically immature cells. Our data demonstrate that COL6 sustains the stem-like properties of GBM cells and supports the maintenance of an aggressive transcriptional program promoting cancer cell proliferation and survival. In particular, we identified a specific subset of COL6-transcriptionally co-regulated genes, required for the response of cells to replicative stress and DNA damage, supporting the concept that COL6 is an essential stimulus for the activation of GBM cell response and resistance to chemotherapy, through the ATM/ATR axis. Altogether, these findings indicate that COL6 plays a pivotal role in GBM tumor biology, exerting a pleiotropic action across different GBM hallmarks, including phenotypic identity and gene transcription, as well as response to treatments, thus providing valuable information for the understanding of the complex microenvironmental cues underlying GBM malignancy.

Targets in the Tumour Matrisome to Promote Cancer Therapy Response

“…Other studies have identified COL11A1 as a functional driver of cancer progression and prognostic biomarker [108][109][110]. A similar body of the literature is emerging supporting pro-tumourigenic functions for COLVI in breast, ovarian [111], pancreatic [112], lung [113], and brain [114] cancers. Clinical intervention here is yet to be explored.…”

New Strategies for Macrophage Re-Education in Cancer: An Update

“…Some components of the extracellular matrix can affect the recruitment of monocytes/macrophages [ 115 , 116 ]. Spondin 2 (SPON2), a matricellular protein 2, is essential for recruiting lymphocytes and initiating immune responses, as well as having a role in tumor progression [ 117 , 118 ].…”

Extracellular Matrix Structure and Interaction with Immune Cells in Adult Astrocytic Tumors

“…Among the different collagen subtypes expressed in glioma, collagen VI was reported to be overexpressed in GBM and high-grade glioma when compared to lower-grade astrocytoma and normal glia (Fujita et al 2008 ). Collagen VI is composed of three different subunits, α1(VI), α2(VI), and α3(VI), whose overexpression in GBM relapses has been related to increased DNA repair and cell survival in response to both radio- and chemotherapy (Cescon et al 2023 ). The aberrant activation of pro-survival signaling pathways including DNA replication and repair genes by collagen VI favor the development of pro-malignant cell behavior in GBM and negatively impact on GBM patients’ prognosis (Cescon et al 2023 ).…”

“…Collagen VI is composed of three different subunits, α1(VI), α2(VI), and α3(VI), whose overexpression in GBM relapses has been related to increased DNA repair and cell survival in response to both radio- and chemotherapy (Cescon et al 2023 ). The aberrant activation of pro-survival signaling pathways including DNA replication and repair genes by collagen VI favor the development of pro-malignant cell behavior in GBM and negatively impact on GBM patients’ prognosis (Cescon et al 2023 ). In particular, collagen VI deposition has been correlated with the enhanced invasion associated with resistance to bevacizumab (Cha et al 2023 ).…”