Proteomic Identification of a Gastric Tumor ECM Signature Associated With Cancer Progression.

Ana M Moreira,Patrícia Carneiro,Rui M Ferreira,John Preto,Hugo Osório,Fátima Carneiro,Perpétua Pinto-Do-Ó,José Barbosa,Raquel Seruca,Joana Figueiredo

doi:10.3389/fmolb.2022.818552

Abstract

The extracellular matrix (ECM) plays an undisputable role in tissue homeostasis and its deregulation leads to altered mechanical and biochemical cues that impact cancer development and progression. Herein, we undertook a novel approach to address the role of gastric ECM in tumorigenesis, which remained largely unexplored. By combining decellularization techniques with a high-throughput quantitative proteomics approach, we have performed an extensive characterization of human gastric mucosa, uncovering its composition and distribution among tumor, normal adjacent and normal distant mucosa. Our results revealed a common ECM signature composed of 142 proteins and indicated that gastric carcinogenesis encompasses ECM remodeling through alterations in the abundance of 24 components, mainly basement membrane proteins. Indeed, we could only identify one de novo tumor-specific protein, the collagen alpha-1(X) chain (COL10A1). Functional analysis of the data demonstrated that gastric ECM remodeling favors tumor progression by activating ECM receptors and cellular processes involved in angiogenesis and cell-extrinsic metabolic regulation. By analyzing mRNA expression in an independent GC cohort available at the TGCA, we validated the expression profile of 12 differentially expressed ECM proteins. Importantly, the expression of COL1A2, LOX and LTBP2 significantly correlated with high tumor stage, with LOX and LTBP2 further impacting patient overall survival. These findings contribute for a better understanding of GC biology and highlight the role of core ECM components in gastric carcinogenesis and their clinical relevance as biomarkers of disease prognosis.

Highlights

Gastric cancer (GC) remains a major clinical burden as one of the most reported malignancies globally, despite a steady decrease in incidence in most developed countries (Arnold et al, 2020)
To characterize the extracellular matrix (ECM) composition of gastric mucosa and potential alterations that may be associated with carcinogenesis, we performed quantitative proteomic analysis of normal distant (ND), normal adjacent (NA) and tumor (T) decellularized ECM samples from nine GC patients (Supplementary Table S1)
The ECM is acknowledged to impact several cancer hallmarks and, matrisome changes have been described for a number of solid cancers (Naba et al, 2014a; Naba et al, 2014b; Acerbi et al, 2015; Laklai et al, 2016)

Summary

Introduction

Gastric cancer (GC) remains a major clinical burden as one of the most reported malignancies globally, despite a steady decrease in incidence in most developed countries (Arnold et al, 2020). Improved detection of GC, at an early stage, would no doubt be crucial to ameliorate both treatment strategies and prediction of patient prognosis. The ECM provides cancer cells with sustained proliferative signals, such as growth factors and chemokines, and shields them from growth suppressors, acting as a diffusion barrier for anti-cancer conventional drugs (Henke et al, 2020) These biochemical and mechanical changes are paramount for cancer progression since they translate into disturbed cell-cell and cell-ECM adhesion, as well as up-regulation of ECM receptors, impacting downstream signaling pathways that promote resistance to cell death, angiogenesis, cancer cell invasion and metastasis (Pickup et al, 2014; Mohan et al, 2020; Figueiredo et al, 2021)

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