Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures

Abstract

Prostate cancer (PCa) is the second leading cause of cancer-associated death in men with therapy resistance acquisition to androgen deprivation treatment and metastasis progression.Understanding the mechanisms of tumor progression to metastatic stage is necessary for the design of therapeutic and prognostic schemes. The main objective of the current study is to determine, using transcriptomic and proteomic analyses on patient derived-xenograft models, whether differentially aggressive PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern, and how this information could be applied in prognostics.Transcriptomic profiling (RNA Sequencing) was performed on PCa PDX models representing different disease stages; BM18 (androgen dependent bone metastasis) and LAPC9 (androgen independent bone metastasis). Using organism-specific reference databases, the humanspecific transcriptome, representing the tumor, was identified and separated from the mousespecific transcriptome (representing the contributing stroma counterpart) from the same PDX tumor samples. To identify proteome changes in the tumor (human) versus the stroma (mouse), we performed human and mouse cell separation using the MACS mouse depletion sorting kit, and subjected protein lysates to quantitative TMT labeling and mass spectrometry. We show

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

“…Several genes of the OB-BMST are associated with a previously identified MFB signature [167] and are CAF markers (Pdgfrb, Sparc) or CAF-recruiting factors (Tgfβ1, Tgfβ3, Fgf2) [44]. Among the most highly expressed genes, a 'seven-gene signature' was identified, not only in the intraosseous xenografts, but also in the stroma of intraprostatic and ectopic VCaP and C4-2B xenografts, and of subcutaneous patient-derived xenografts [44,168]. This suggests that the osteoblastic stromal signature is, to some extent, conserved and thus represents a specific response to the osteoblastic phenotype of these tumor cells.…”

“…Re-expression of TNC in the bone could be a factor attracting disseminated PCa cells in this site, supporting the idea that cancer cells tend to metastasize in microenvironments similar to the primary tumor. Moreover, a gene expression analysis of the stroma of bone metastasis patient-derived xenograft models suggests that stromal TNC expression is modulated by the presence/absence of androgens [168].…”