A pan-cancer analysis of matrisome proteins reveals CTHRC1and LOXL2 as major ECM regulators across cancers

Abstract

AbstractThe extracellular matrix as part of the tumor microenvironment can regulate cancer cell growth and progression. Using TCGA data from 30 cancer types, the top 5% of matrisome genes with amplifications or deletions that affect survival in cancers were identified. Eight of these genes show altered expression in ~50% or more cancers affecting survival in ~20% or more. Among them SNED1 is the most downregulated and CTHRC1 and LOXL2 most upregulated. Differential gene expression analysis of SNED-1 did not identify any genes it regulates across cancers, while CTHRC1 and LOXL2 affected 19 and 5 genes respectively in 3 or more cancers. STRING analysis of these genes classified them as ‘extracellular’, involved prominently in ECM organization. Their correlation and co-occurrence in context of their effect on survival and staging of the disease identified MMP13, POSTN and SFRP4 along with COL11A1, COL10A1, COL1A1, ADAMTS12 and PPAPDC1A as possible interactors of CTHRC1 and LOXL2 in cancers. These are implicated in collagen organization, making it vital to matrisome regulation of cancers. Clinical Proteomic Tumor Analysis Consortium data confirms the changes in expression of these genes along with CTHRC1 and LOXL2 in breast and lung cancer, further supporting their implication as vital pan-cancer matrisome mediators.HighlightsCTHRC1 and LOXL2 are prominently upregulated pan-cancer matrisome genes.High CTHRC1 and LOXL2 expression is associated with disease progression and poor survival in cancers.CTHRC1 with POSTN, MMP13 and SFRP4 and LOXL2 with COL11A1, COL10A1, COL1A1, ADAMTS12 and PPAPDC1A drive matrisome regulation of cancers.CTHRC1 and LOXL2 could prominently drive collagen organization and function across cancers.