Mass-spectrometry-based proteomic data on human tumors—combined with corresponding multi-omics data—present opportunities for systematic and pan-cancer proteogenomic analyses. Here, we assemble a compendium dataset of proteomics data of 2002 primary tumors from 14 cancer types and 17 studies. Protein expression of genes broadly correlates with corresponding mRNA levels or copy number alterations (CNAs) across tumors, but with notable exceptions. Based on unsupervised clustering, tumors separate into 11 distinct proteome-based subtypes spanning multiple tissue-based cancer types. Two subtypes are enriched for brain tumors, one subtype associating with MYC, Wnt, and Hippo pathways and high CNA burden, and another subtype associating with metabolic pathways and low CNA burden. Somatic alteration of genes in a pathway associates with higher pathway activity as inferred by proteome or transcriptome data. A substantial fraction of cancers shows high MYC pathway activity without MYC copy gain but with mutations in genes with noncanonical roles in MYC. Our proteogenomics survey reveals the interplay between genome and proteome across tumor lineages.

Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.

Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor ( M-Csf / Csf1 ). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN). The Pb-Csf1 prostate luminal cells exhibit increased stem cell features and epithelial-to-mesenchymal transition. Human prostate cancer patients with high CSF-1 expression display similar transcriptional alterations with the Pb-Csf1 model. P53 knockout alleviates senescence but fails to progress PIN lesions. Ablating epithelial Gp130 but not Il1r1 substantially blocks PIN lesion formation. The androgen receptor (AR) is downregulated in Pb-Csf1 mice. ChIP-Seq analysis reveals altered AR binding in 2482 genes although there is no significant widespread change in global AR transcriptional activity. Collectively, our study demonstrates that increased macrophage infiltration causes PIN formation but fails to transform prostate cells.

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