Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures
1
Urology Research Laboratory, Department for BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland
2
Oncogenomics Laboratory, Department for BioMedical Research, University of Bern, Murtenstrasse 40, 3008 Bern, Switzerland
3
Lindenhofspital Bern, Prostate Center Bern, 3012 Bern, Switzerland
4
Proteomics Core Facility, EMBL Heidelberg, Meyerhofstraße 1, 69117 Heidelberg, Germany
5
Department of Urology, Inselspital, Anna Seiler Haus, Bern University Hospital, 3010 Bern, Switzerland
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2020, 12(12), 3786; https://doi.org/10.3390/cancers12123786
Received: 1 December 2020 / Accepted: 10 December 2020 / Published: 15 December 2020
(This article belongs to the Special Issue Urological Cancer 2020)
Simple Summary
Currently, there is a need for prognostic tools that can stratify patients, who present with primary disease, based on whether they are at low or high risk for drug resistant and hormone-independent lethal metastatic prostate cancer. The aim of our study was to assess the potentially added value of tumor microenvironment (stroma) components for the characterisation of prostate cancer. By utilising patient derived-xenograft models we show that the molecular properties of the stroma cells are highly responsive to androgen hormone levels, and considerable ECM remodelling processes take place not only in androgen-dependent but also in androgen-independent tumor models. Transcriptomic mechanisms linked to osteotropism are conserved in bone metastatic xenografts, even when implanted in a different microenvironment. A stroma-specific gene list signature was identified, which highly correlates with Gleason score, metastasis progression and progression-free survival, and thus could potentially complement current patient stratification methods.
Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. RNA sequencing was performed on the PCa PDXs BM18 (castration-sensitive) and LAPC9 (castration-resistant), representing different disease stages. Using organism-specific reference databases, the human-specific transcriptome (tumor) was identified and separated from the mouse-specific transcriptome (stroma). To identify proteomic changes in the tumor (human) versus the stroma (mouse), we performed human/mouse cell separation and subjected protein lysates to quantitative Tandem Mass Tag labeling and mass spectrometry. Tenascin C (TNC) was among the most abundant stromal genes, modulated by androgen levels in vivo and highly expressed in castration-resistant LAPC9 PDX. The tissue microarray of primary PCa samples (n = 210) showed that TNC is a negative prognostic marker of the clinical progression to recurrence or metastasis. Stroma markers of osteoblastic PCa bone metastases seven-up signature were induced in the stroma by the host organism in metastatic xenografts, indicating conserved mechanisms of tumor cells to induce a stromal premetastatic signature. A 50-gene list stroma signature was identified based on androgen-dependent responses, which shows a linear association with the Gleason score, metastasis progression and progression-free survival. Our data show that metastatic PCa PDXs, which differ in androgen sensitivity, trigger differential stroma responses, which show the metastasis risk stratification and prognostic biomarker potential.
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MDPI and ACS Style
Karkampouna, S.; De Filippo, M.R.; Ng, C.K.Y.; Klima, I.; Zoni, E.; Spahn, M.; Stein, F.; Haberkant, P.; Thalmann, G.N.; Kruithof-de Julio, M. Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures. Cancers 2020, 12, 3786.
AMA Style
Karkampouna S, De Filippo MR, Ng CKY, Klima I, Zoni E, Spahn M, Stein F, Haberkant P, Thalmann GN, Kruithof-de Julio M. Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures. Cancers. 2020; 12(12):3786.
Chicago/Turabian StyleKarkampouna, Sofia; De Filippo, Maria R.; Ng, Charlotte K.Y.; Klima, Irena; Zoni, Eugenio; Spahn, Martin; Stein, Frank; Haberkant, Per; Thalmann, George N.; Kruithof-de Julio, Marianna. 2020. "Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures" Cancers 12, no. 12: 3786.
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