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

View ORCID ProfileS. Karkampouna, M.R. De Filippo, C.Y. Ng, I. Klima, View ORCID ProfileE. Zoni, M. Spahn, F. Stein, P. Haberkant, G.N. Thalmann, View ORCID ProfileM.Kruithof de Julio
doi: https://doi.org/10.1101/2020.04.03.018143
S. Karkampouna
1Department for Biomedical Research, Urology Research laboratory, University of Bern, Switzerland
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M.R. De Filippo
1Department for Biomedical Research, Urology Research laboratory, University of Bern, Switzerland
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C.Y. Ng
2Department for BioMedical Research, Oncogenomics Laboratory, University of Bern, Switzerland
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I. Klima
1Department for Biomedical Research, Urology Research laboratory, University of Bern, Switzerland
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E. Zoni
1Department for Biomedical Research, Urology Research laboratory, University of Bern, Switzerland
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M. Spahn
3Hirslanden clinic, Zurich, Switzerland
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F. Stein
4Proteomics Core Facility, EMBL Heidelberg, Meyerhofstraße 1, 69117 Heidelberg, Germany
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P. Haberkant
4Proteomics Core Facility, EMBL Heidelberg, Meyerhofstraße 1, 69117 Heidelberg, Germany
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G.N. Thalmann
1Department for Biomedical Research, Urology Research laboratory, University of Bern, Switzerland
5Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland
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M.Kruithof de Julio
1Department for Biomedical Research, Urology Research laboratory, University of Bern, Switzerland
5Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland
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  • For correspondence: marianna.kruithofdejulio@dbmr.unibe.ch
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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 human-specific transcriptome, representing the tumor, was identified and separated from the mouse-specific 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 that tenascin C is one of the most abundant stromal genes in bone metastasis PCa PDXs, is modulated by androgen levels in vivo and is highly expressed in castration resistant LAPC9 PDX compared to castration sensitive BM18 PDX. Tissue microarray of primary PCa samples (N=210) was used to evaluate the potential of TNC to act as a metastasis prognosis marker. Low number of TNC-positive cells were associated with statistically significant clinical progression to local recurrence or metastasis, compared to high TNC-positive group. Our data showed that metastatic PCa PDXs that differ in androgen sensitivity trigger a differential stroma response suggesting that stroma was influenced by tumor cues. Selected stromal markers of osteoblastic PCa induced bone metastases, were induced in the microenvironment of the host organism in metastatic xenografts, although implanted in a non-bone site, indicating a conserved mechanism of tumor cells to induce a stromal pre-metastatic signature with high potential prognostic or diagnostic value.

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Posted April 04, 2020.
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Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures
S. Karkampouna, M.R. De Filippo, C.Y. Ng, I. Klima, E. Zoni, M. Spahn, F. Stein, P. Haberkant, G.N. Thalmann, M.Kruithof de Julio
bioRxiv 2020.04.03.018143; doi: https://doi.org/10.1101/2020.04.03.018143
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Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures
S. Karkampouna, M.R. De Filippo, C.Y. Ng, I. Klima, E. Zoni, M. Spahn, F. Stein, P. Haberkant, G.N. Thalmann, M.Kruithof de Julio
bioRxiv 2020.04.03.018143; doi: https://doi.org/10.1101/2020.04.03.018143

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