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  • br The most significant gene sets associated with the


    The most significant gene sets associated with the core secre-tome were related to ECM turnover, cell-matrix adhesion, and signaling processes involving the ECM or immunity and inflam-mation (Figure 2C). Furthermore, the secretome expression in-crease associated with the epithelial-mesenchymal transition (EMT) underscores the importance of the cancer secretome in metastatic and invasive processes, regardless of cancer type. Gene sets related to glycosaminoglycan (GAG) binding, specif-ically heparin, were among the most significant coordinated de-creases in secretome expression. As the genes within these sets encode for proteins associated with cell-matrix and basement membrane adhesion, their decreased expression further sup-ports a contribution of the secretome to a more migratory and invasive phenotype.
    The Effects of Tumor Purity on Core Secretome Expression Profiles
    Tumors are infiltrated to varying degrees by non-cancerous cells, such as stromal or immune Okadaic acid (Hanahan and Weinberg, 2011). Molecular profiles of bulk tumor samples will therefore contain signatures from these infiltrating cells, which can obscure or be misinterpreted as those originating from tumor cells. To assess whether infiltrating cells were responsible for any of the identified features of the core secretome, we repeated the analyses using only tumor samples with a consensus purity estimate (CPE) (Aran et al., 2015) of at least 80% (Figure S2). The major features remained largely unchanged, supporting their association with the cancerous cells themselves. For example, all 16 genes in the top 1% of the core secretome exhibited a sig-nificant expression decrease in most or all of the included cancer 
    types, and 11 of those genes were also present in the top 1% for the original analysis. Functions related to ECM turnover were again enriched among core secretome expression increases, although to a lesser extent when considering only high-purity tumor samples.
    Cancer Type-Specific Secretome Expression Profiles Following the investigation of coordinated pan-cancer secre-tome shifts, we were interested in evaluating the cancer types individually and determining which processes and functions ex-hibited strong changes within each type. We therefore conduct-ed a directional and non-directional GSA of the differential expression (DE) analysis results, in which the direction of expres-sion fold changes were included or excluded, respectively (STAR Methods; Va¨remo et al., 2013).
    In the directional GSA (Figure 3A), cancer types generally ex-hibited expression increases associated with ECM components and metalloprotease activity; however, cholangiocarcinoma (CHOL) and head and neck squamous cell carcinoma (HNSC) accounted for the most significant increases, whereas prostate adenocarcinoma (PRAD), bladder urothelial carcinoma (BLCA), uterine corpus endometrial carcinoma (UCEC), and the kidney cancers displayed no coordinated change or even Okadaic acid a modest decrease in expression. For these latter cancers, the non-direc-tional GSA results (Figure 3B) revealed significant expression changes associated with these processes, but it was a mix of increases and decreases rather than a coordinated shift in one direction. Conversely, expression decreases related to adhesion and GAG binding were observed across many cancer types, with the most significant decreases occurring in kidney chromophobe (KICH), BLCA, and UCEC. Again, when ignoring the direction of expression change, virtually all of the cancers exhibited significant shifts in the secretome related to these functions. These results suggest that different cancer types are shifting their secretome expression in accordance with a common set of molecular functions, but the extent and direction of these changes are often tuned specifically to the tissue of origin.