Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer

Xiaolei Shi; Abderrahman Day; Hannah E. Bergom; Sydney Tape; Sylvan C. Baca; Zoi E. Sychev; Gabrianne Larson; Asha Bozicevich; Justin M. Drake; Nicholas A Zorko; Jinhua Wang; Charles J. Ryan; Emmanuel S. Antonarakis; Justin Hwang

doi:10.1038/s41698-022-00323-2

Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer

Xiaolei Shi, Abderrahman Day, Hannah E. Bergom, Sydney Tape, Sylvan C. Baca, Zoi E. Sychev, Gabrianne Larson, Asha Bozicevich, Justin M. Drake, Nicholas A Zorko, Jinhua Wang, Charles J. Ryan, Emmanuel S. Antonarakis, Justin Hwang

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Abstract

B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.

Original language	English (US)
Article number	80
Journal	npj Precision Oncology
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s41698-022-00323-2
State	Published - Dec 2022

Bibliographical note

Funding Information:
We thank our funding source Ray of Light Foundation (University of Minnesota) and Randy Shaver Cancer Research and Community Fund to support this work. Ray of Light Foundation award from Division of Hematology, Oncology, and Transplantation, University of Minnesota was allocated to the research efforts of J.H. and H.E.B. Randy Shaver Cancer Research and Community Fund from University of Minnesota was allocated to the research efforts of J.H., E.S.A., and N.Z. Some of the figures shown here were created with https://biorender.com/ . We acknowledge TCGA for data generated by TCGA Research Network: https://www.cancer.gov/tcga .

Publisher Copyright:
© 2022, The Author(s).

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Shi, X., Day, A., Bergom, H. E., Tape, S., Baca, S. C., Sychev, Z. E., Larson, G., Bozicevich, A., Drake, J. M., Zorko, N. A., Wang, J., Ryan, C. J., Antonarakis, E. S., & Hwang, J. (2022). Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer. npj Precision Oncology, 6(1), Article 80. https://doi.org/10.1038/s41698-022-00323-2

Shi, X, Day, A, Bergom, HE, Tape, S, Baca, SC, Sychev, ZE, Larson, G, Bozicevich, A, Drake, JM , Zorko, NA , Wang, J , Ryan, CJ , Antonarakis, ES & Hwang, J 2022, 'Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer', npj Precision Oncology, vol. 6, no. 1, 80. https://doi.org/10.1038/s41698-022-00323-2

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abstract = "B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.",

author = "Xiaolei Shi and Abderrahman Day and Bergom, {Hannah E.} and Sydney Tape and Baca, {Sylvan C.} and Sychev, {Zoi E.} and Gabrianne Larson and Asha Bozicevich and Drake, {Justin M.} and Zorko, {Nicholas A} and Jinhua Wang and Ryan, {Charles J.} and Antonarakis, {Emmanuel S.} and Justin Hwang",

note = "Funding Information: We thank our funding source Ray of Light Foundation (University of Minnesota) and Randy Shaver Cancer Research and Community Fund to support this work. Ray of Light Foundation award from Division of Hematology, Oncology, and Transplantation, University of Minnesota was allocated to the research efforts of J.H. and H.E.B. Randy Shaver Cancer Research and Community Fund from University of Minnesota was allocated to the research efforts of J.H., E.S.A., and N.Z. Some of the figures shown here were created with https://biorender.com/ . We acknowledge TCGA for data generated by TCGA Research Network: https://www.cancer.gov/tcga . Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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AU - Baca, Sylvan C.

AU - Sychev, Zoi E.

AU - Larson, Gabrianne

AU - Bozicevich, Asha

AU - Drake, Justin M.

AU - Zorko, Nicholas A

AU - Wang, Jinhua

AU - Ryan, Charles J.

AU - Antonarakis, Emmanuel S.

AU - Hwang, Justin

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N2 - B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.

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Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer

Abstract

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