Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer

Marina N. Sharifi; Eric Feng; Nicholas R. Rydzewski; Amy K. Taylor; Jamie M. Sperger; Yue Shi; Kyle T. Helzer; Matthew L. Bootsma; Viridiana Carreno; Alex H. Chang; Luke A. Nunamaker; Grace C. Blitzer; Tianfu Andy Shang; Aishwarya Subramanian; Anders Bjartell; Andreas Josefsson; Pernilla Wikström; Emily Feng; Manish Kohli; Rendong Yang; Scott M. Dehm; Eric J. Small; Rahul Aggarwal; David A. Quigley; Joshua M. Lang; Shuang G. Zhao; Martin Sjöström

doi:10.1002/1878-0261.70001

Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer

Marina N. Sharifi, Eric Feng, Nicholas R. Rydzewski, Amy K. Taylor, Jamie M. Sperger, Yue Shi, Kyle T. Helzer, Matthew L. Bootsma, Viridiana Carreno, Alex H. Chang, Luke A. Nunamaker, Grace C. Blitzer, Tianfu Andy Shang, Aishwarya Subramanian, Anders Bjartell, Andreas Josefsson, Pernilla Wikström, Emily Feng, Manish Kohli, Rendong YangScott M. Dehm, Eric J. Small, Rahul Aggarwal, David A. Quigley, Joshua M. Lang, Shuang G. Zhao, Martin Sjöström^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.

Original language	English (US)
Journal	Molecular oncology
DOIs	https://doi.org/10.1002/1878-0261.70001
State	Accepted/In press - 2025

Funding

We would like to acknowledge funding from the National Institutes of Health [grant numbers DP2 OD030734 to SGZ, 1UH2CA260389 to SGZ, JML, R01CA247479 to JML, R01CA259388 to RY, R35GM142441 to RY, R01CA174777 to SMD, R01CA270539 to SMD, R01CA276269 to SMD, JML, NCI SPORE 1P50CA275741 support for DAQ], Department of Defense [grant numbers PC190039 to SGZ, PC200334 to SGZ, JML, PC180469 to JML, PC220240 to MNS, W81XWH\u201022\u20101\u20100833 and HT94252410252 to DAQ], Prostate Cancer Foundation (Movember Foundation\u2014PCF Challenge Award to JML, 2022 Janssen\u2014PCF Special Challenge Award to DAQ, 2022 Point Biopharma Young VAlor Investigator Award to MNS, 2021 Michael and Patricia Berns\u2010PCF Young Investigator Award to MS), the Benioff Initiative for Prostate Cancer Research (DAQ) the University of Wisconsin Office of the Vice Chancellor for Research and Graduate Education (PICI award to SGZ), the Doris Duke Charitable Foundation (Physician Scientist Fellowship #2021088 to MNS), the Swedish Cancer Society (Cancerfonden, Junior Clinical Investigator Award to MS and 21 1856 Pj to PW), the Swedish Prostate Cancer Foundation (Prostatacancerf\u00F6rbundet, to MS and PW), Knut and Alice Wallenberg Foundation (AJ), and Hjelms stiftelse f\u00F6r medicinsk forskning (to AB and MS). Shared research services at the UWCCC are supported by a National Institutes of Health Cancer Center Support Grant [grant number P30 CA014520]. KTH has a family member who is an employee of Epic Systems. YS reports employment at Tempus with restricted stock units. MB has a family member who is an employee of Luminex. SGZ reports unrelated patents licensed to Veracyte, and that a family member is an employee of Artera and holds stock in Exact Sciences. SMD reports consulting relationships with BMS, Oncternal therapeutics, Janssen R&D/J&J and a grant from Pfizer/Astellas/Medivation (the grant was submitted to Medivation, ultimately funded by Astellas and then moved to Pfizer). EJS reports honoraria from Janssen for serving on Advisory Board and honoraria and stock options from Fortis Therapeutics. MNS reports institutional research support from Novartis. MS reports speaker fees from Astellas and consulting fees for serving on Advisory Board from Veracyte/Adelphi Targis.

Keywords

biomarker
gene expression
metastatic castration-resistant prostate cancer
precision medicine
prognosis

ASJC Scopus subject areas

Molecular Medicine
Oncology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/1878-0261.70001

Cite this

Sharifi, M. N., Feng, E., Rydzewski, N. R., Taylor, A. K., Sperger, J. M., Shi, Y., Helzer, K. T., Bootsma, M. L., Carreno, V., Chang, A. H., Nunamaker, L. A., Blitzer, G. C., Shang, T. A., Subramanian, A., Bjartell, A., Josefsson, A., Wikström, P., Feng, E., Kohli, M., ... Sjöström, M. (Accepted/In press). Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer. Molecular oncology. https://doi.org/10.1002/1878-0261.70001

@article{87d96b9606e745da94079630d5e5eca0,

title = "Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer",

abstract = "Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.",

keywords = "biomarker, gene expression, metastatic castration-resistant prostate cancer, precision medicine, prognosis",

author = "Sharifi, {Marina N.} and Eric Feng and Rydzewski, {Nicholas R.} and Taylor, {Amy K.} and Sperger, {Jamie M.} and Yue Shi and Helzer, {Kyle T.} and Bootsma, {Matthew L.} and Viridiana Carreno and Chang, {Alex H.} and Nunamaker, {Luke A.} and Blitzer, {Grace C.} and Shang, {Tianfu Andy} and Aishwarya Subramanian and Anders Bjartell and Andreas Josefsson and Pernilla Wikstr{\"o}m and Emily Feng and Manish Kohli and Rendong Yang and Dehm, {Scott M.} and Small, {Eric J.} and Rahul Aggarwal and Quigley, {David A.} and Lang, {Joshua M.} and Zhao, {Shuang G.} and Martin Sj{\"o}str{\"o}m",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

year = "2025",

doi = "10.1002/1878-0261.70001",

language = "English (US)",

journal = "Molecular oncology",

issn = "1574-7891",

publisher = "John Wiley and Sons Ltd",

}

Sharifi, MN, Feng, E, Rydzewski, NR, Taylor, AK, Sperger, JM, Shi, Y, Helzer, KT, Bootsma, ML, Carreno, V, Chang, AH, Nunamaker, LA, Blitzer, GC, Shang, TA, Subramanian, A, Bjartell, A, Josefsson, A, Wikström, P, Feng, E, Kohli, M, Yang, R, Dehm, SM, Small, EJ, Aggarwal, R, Quigley, DA, Lang, JM, Zhao, SG & Sjöström, M 2025, 'Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer', Molecular oncology. https://doi.org/10.1002/1878-0261.70001

TY - JOUR

T1 - Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer

AU - Sharifi, Marina N.

AU - Feng, Eric

AU - Rydzewski, Nicholas R.

AU - Taylor, Amy K.

AU - Sperger, Jamie M.

AU - Shi, Yue

AU - Helzer, Kyle T.

AU - Bootsma, Matthew L.

AU - Carreno, Viridiana

AU - Chang, Alex H.

AU - Nunamaker, Luke A.

AU - Blitzer, Grace C.

AU - Shang, Tianfu Andy

AU - Subramanian, Aishwarya

AU - Bjartell, Anders

AU - Josefsson, Andreas

AU - Wikström, Pernilla

AU - Feng, Emily

AU - Kohli, Manish

AU - Yang, Rendong

AU - Dehm, Scott M.

AU - Small, Eric J.

AU - Aggarwal, Rahul

AU - Quigley, David A.

AU - Lang, Joshua M.

AU - Zhao, Shuang G.

AU - Sjöström, Martin

PY - 2025

Y1 - 2025

N2 - Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.

AB - Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.

KW - biomarker

KW - gene expression

KW - metastatic castration-resistant prostate cancer

KW - precision medicine

KW - prognosis

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UR - http://www.scopus.com/inward/citedby.url?scp=85218705563&partnerID=8YFLogxK

U2 - 10.1002/1878-0261.70001

DO - 10.1002/1878-0261.70001

M3 - Article

C2 - 39985777

AN - SCOPUS:85218705563

SN - 1574-7891

JO - Molecular oncology

JF - Molecular oncology

ER -

Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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