23Background: Recent sequencing efforts unveil genomic landscapes of the tumor 24 microenvironment. Yet, little is known about the extent to which matrisome pattern is 25 conserved in progressive tumors across diverse cancer types, and thus its clinical impact 26 remains largely unexplored. 27Findings: Using a newly generated, unified data resource, we conducted cross-platform 28 assessment of a measure of altered extra-cellular matrix (ECM) composition and remodeling 29 associated with tumor progression, termed as the matrisome index (TMI). Parallel analyses 30 with TCGA in over 30,000 patient-derived biopsies revealed that TMI is closely associated 31 with mutational load, tumor histopathology, and predictive of patient outcomes. We found an 32 enrichment of specific tumor-infiltrating immune cell populations, signatures predictive of 33 immunotherapy resistance, and several immune checkpoints in tumors with high TMI, 34suggesting potential role of ECM interaction with immunophenotyes and tumor immune 35 escape mechanisms. Both epithelial cancer cells and carcinoma-associated fibroblasts are 36 potential cellular contributors of such deregulated matrisome. 37Conclusions: Despite wide spectrum of genetic heterogeneity and dynamic nature, 38 matrisome abnormalities are integral to disease progression. Our resource of a curated 39 compendium of 8,386 genome-wide profiles, molecular and clinical associations, and 40 matrisome-tumor genotype-immunophenotype relationships identify potentially actionable 41 immune targets that may guide personalized immunotherapy. 42
43We further define the pan-cancer matrisome landscape by exploring previously unknown 69 features of matrix remodeling and their impact on tumor genotypes and immunophenotypes. 70Using this newly curated MMD together with 12 TCGA cohorts, we found robust 71 associations of tumor-promoting matrix composition with genomic instability, molecular and 72 clinical features, and immune infiltrate composition. At the center of our results is the 73 promising clinical applicability of TMI to predict immunotherapeutic responsiveness and the 74 identification of specific immune targets that may be selectively efficacious in subset of 75 matrisome-deregulated carcinomas. 76Results 77
Patterns of deregulated matrisome genes are conserved in various malignancies 78Given that the initial TMI was derived from lung cancer, we first questioned the extent to 79 which genome-wide DE patterns of lung cancer would be shared across various carcinomas. 80Conducting cross-platform analysis with TCGA, we found that DE patterns of lung cancers 81 were comparable to that of breast, ovarian, bladder, colorectal, and prostate cancers, 82 regardless of assayed platforms (Tables S3 and S4). Recent pan-cancer studies have revealed 83 some cancers of these tumor types were classified into common molecular subtypes [8, 9]. 84Assessing the initial 29-matrisome-gene signature at the individual gene level, we found that 85 many genes were consistently positioned in the top of the ranked DE g...