**5. Conclusions**

In this proof-of-concept study, the molecular profile of the stroma in prostate cancer was shown to be responsive to androgen deprivation even in advanced, androgen-independent bone metastasis prostate cancer. We identified a stroma-specific gene expression signature that correlates with the Gleason score and metastatic disease progression of prostate cancer. Given the inevitable drug resistance to androgen deprivation therapies, stroma biomarker identification associated with resistance acquisition may complement standard histopathology and genomic evaluations for improved stratification of patients at high risk.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2072-6694/12/12/3786/s1: Figure S1. Related to Figure 2. Human transcriptomic profile of BM18 and LAPC9 tumors. Figure S2. Related to Figure 2. Human and mouse ratios of RNA-Seq transcript levels in intact and castrated settings. Figure S3. Related to Figure 5. Pathways enriched in the stroma of the CRPC LAPC9 compared to the BM18. Figure S4. Related to Figure 7. PSA progression in cases with positive surgical margins or lymph nodes status. Figure S5. Related to Figure 9. Correlations and prognostic performances of the C1, C2, C3 and C4 signatures compared to the previously identified stroma signatures. Table S1. Venn Euler diagrams. Table S2: Lists of enriched GO and KEGG pathways (attached as an Excel file). Table S3. Statistical test TNC expression in patient groups of different pT Stage classification in the high risk PCa TMA. Table S4. Stroma signature gene lists. Table S5. Human gene lists of Ob-BMST and C1-C4 signatures.

**Author Contributions:** Conceptualization, S.K. and M.K.d.J.; formal analysis, S.K., M.R.D.F., C.K.Y.N., E.Z., F.S. and P.H.; funding acquisition, S.K., G.N.T. and M.K.d.J.; investigation, S.K. and I.K.; methodology, E.Z. and P.H.; project administration, M.K.d.J.; resources, M.S., G.N.T. and M.K.d.J.; software, P.H.; supervision, M.K.d.J.; writing—original draft, S.K., F.S. and M.K.d.J. and writing—review and editing, M.R.D.F., C.K.Y.N., E.Z. and G.N.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This project received funding from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Individual Fellowship (S.K.), grant agreement no. 748836 (STOPCa) and additional funding from the Swiss National Science Foundation (320030L\_189369 to G.N.Thalmann).

**Acknowledgments:** The authors would like to thank the Microscopy Facility of the University of Bern, Francesco Bonollo, Peter C Gray, Salvatore Piscuoglio and all the members of the DBMR Urology laboratory for critical discussions and technical support.

**Conflicts of Interest:** The authors declare no conflict of interest.

**Data Availability:** The sequencing data have been submitted to the European Genome-Phenome Archive under the accession number EGAS00001004770.
