Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis

Abstract

The extracellular matrix (ECM), a major component of the tumor microenvironment, promotes local invasion to drive metastasis. Here, we describe a method to study whole-tissue ECM effects from disease states associated with metastasis on tumor cell phenotypes and identify the individual ECM proteins and signaling pathways that are driving these effects. We show that decellularized ECM from tumor-bearing and obese mammary glands drives TNBC cell invasion. Proteomics of the ECM from the obese mammary gland led us to identify full-length collagen VI as a novel driver of TNBC cell invasion whose abundance in tumor stroma increases with body mass index in human TNBC patients. Last, we describe the mechanism by which collagen VI contributes to TNBC cell invasion via NG2-EGFR cross-talk and MAPK signaling. Overall, these studies demonstrate the value of decellularized ECM scaffolds obtained from tissues to identify novel functions of the ECM.

The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors

“…Currently, 3D systems with tunable ECM stiffness, bioprinted 3D cell culture systems incorporating TME, systems based on 3D culture of patient's tumor tissue, and systems utilizing decellularized ECM from the patient's tumor have been established (82)(83)(84)(85). Such systems have a clear potential for use in translational oncology.…”

“…Three-dimensional cell culture systems also have proven to be a "biomarkers goldmine"-a valuable tool for biomarker identification (88). For example, using 3D culture model with decellularized ECM scaffolds (dECM) allowed to identify fulllength Collagen VI as a driver of breast cancer cell invasion in obesity and metastasis (89). In colorectal cancer, the patterns of expression of miRNA dependent on 3D microenvironment have been characterized, and one of them (miR-142-5p) was identified as a theranostic biomarker (90).…”

Identification of disease-promoting stromal components by comparative proteomic and transcriptomic profiling of canine mammary tumors using laser-capture microdissected FFPE tissue

“…As a regulator of PI3K signaling, the expression IGFBP2 is strongly correlated with grade of malignancy in many tumors and especially in breast cancer [59] . Collagen VI has been recently identified as driver of invasion and metastasis of breast cancer and high protein levels of Collagen VI have been found by bulk tumor proteomic analysis of more than 500 human cancers 60 , 61 , 62 . Strongly elevated levels of both POSTN and FN1 are well documented in a wide variety of tumors, including breast cancer, and have been shown to promote tumor invasion and metastasis through manifold effects on different cancer hallmarks (reviewed in [ 63 , 64 ]).…”

Systemic Multi-Omics Analysis Reveals Amplified P4HA1 Gene Associated With Prognostic and Hypoxic Regulation in Breast Cancer

“…P4HA1 has recently been found to overexpress in gliomas and HNSCC; its expression associated with tumor microvessel density ( Li et al, 2019 ). Recent studies have shown that increased production of collagen is linked to BC progression, adhesion, and invasion ( Xiong et al, 2018 ; Wishart et al, 2020 ).…”