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Characterization of prostate cancer adrenal metastases: dependence upon androgen receptor signaling and steroid hormones

Prostate Cancer and Prostatic Diseases volume 26, pages 751–758 (2023)Cite this article

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Abstract

Background

Prostate cancer (PCa) typically spreads to the bone, and this distribution is attributed to the central role of the microenvironment in progression. However, metastasis to the adrenal glands, while not as common, does occur. The biology that accounts for adrenal metastases may be attributed to the unique local steroid metabolome and co-clinical characterization may elucidate the role steroid biosynthesis plays in PCa progression.

Methods

Three patients with metastatic PCa who had archived tumor tissue from an adrenalectomy were retrospectively identified, and one adrenal metastasis was developed into a xenograft (MDA-PCa-250). The adrenal metastases were characterized by performing somatic DNA whole exome sequencing (WES), RNA-Seq, immunohistochemistry (IHC), and steroid metabolite quantitation. The influence of steroid metabolites on adrenal metastasis cells and tumor growth was tested in vitro and in vivo.

Results

Clinically, adrenalectomy was performed during castration-resistant oligometastatic disease, and two men experienced resensitization to leuprolide. Somatic DNA WES revealed heterogeneous alterations in tumor suppressor and DNA damage repair pathway genes. Adrenal metastases had active androgen receptor (AR) signaling by IHC, and RNA-Seq supported a potential role for adrenal androgen precursor metabolism in activating the AR. Steroid quantitation suggested the adrenal androgen precursors were converted into testosterone in these metastases, and stable isotope tracing of an organoid from MDA-PCa-250 confirmed the capability of adrenal metastases to biosynthesize testosterone from adrenal precursors. In vitro testing of a cell line derived from MDA-PCa-250 showed that testosterone and cortisol stimulated tumor cell growth. In vivo experiments demonstrated that MDA-PCa-250 grew in intact mice with circulating testosterone, but not in castrated mice.

Conclusions

PCa adrenal metastases depend upon AR signaling driven by androgen precursors, androstenedione and dehydroepiandrosterone, available in the microenvironment, despite the presence of heterogeneous somatic DNA alterations. Moreover, MDA-PCa-250 provides a preclinical model that can recapitulate the unique androgen-dependence of adrenal metastases.

Clinical trial registration

This study does not report the clinical results of a clinical trial, but it does use samples from a completed clinical trial that is registered with clinicaltrials.gov (NCT01254864).

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Fig. 1: Steroid metabolite measurements from prostate cancer adrenal metastases and controls.
Fig. 2: The effect of testosterone and cortisol on proliferation of MDA-PCa-250.
Fig. 3: Growth curves of a patient-derived xenograft of a prostate cancer adrenal metastasis (MDA-PCa-250) in castrated and hormonally intact mice.

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Data availability

Data is available to any reader upon request. Please email the corresponding author to request the data.

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Funding

The experiments reported in this study were funded by the David H. Koch Center for Applied Research of Genitourinary Cancers. AWH is supported by a Conquer Cancer Foundation Young Investigator Award, the Rob Heyvaert and Paul Heynen Prostate Cancer Foundation Young Investigator Award, and philanthropic donations from Michael and Patricia Berns.

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Author notes

  1. These authors contributed equally: Minas J Sakellakis, Andrew W. Hahn.

Authors and Affiliations

  1. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Minas J. Sakellakis, Sumankalai Ramachandran, Anh Hoang, Jian H. Song, Hirak S. Basu, Peter Sheperd, Daniel E. Frigo, Sue-Hwa Lin, Theocharis Panaretakis, Nora Navone, Christopher J. Logothetis & Mark A. Titus

  2. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Andrew W. Hahn

  3. Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Miao Zhang & Patricia Troncoso

  4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jingjing Liu, Feng Wang & Jianhua Zhang

  5. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Xuemei Wang

  6. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Daniel E. Frigo

  7. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sue-Hwa Lin

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  1. Minas J. Sakellakis
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Contributions

Concept and design: Christopher J. Logothetis and Mark A. Titus. Collection and assembly of data: Minas J Sakellakis, Andrew W. Hahn, Sumankalai Ramachandran, Anh Hoang, Jian H. Song, Peter Sheperd, Miao Zhang, Patricia Troncoso, and Mark A. Titus. Data analysis and interpretation: All authors. Manuscript writing: All authors. Final approval of manuscript: All authors.

Corresponding authors

Correspondence to Christopher J. Logothetis or Mark A. Titus.

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Competing interests

DEF has received research funding from GTx, Inc and has a familial relationship with Hummingbird Bioscience, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals, and Barricade Therapeutics. CJL reports commercial research grants from Janssen, ORIC Pharmaceuticals, Novartis, Aragon Pharmaceuticals, and honoraria from Merck, Sharp, and Dohme, Bayer, and Amgen. The other authors report no potential conflicts of interest.

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Informed consent was obtained from each patient for the studies described above and subsequent publication.

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This study was approved by the University of Texas MD Anderson Cancer Center Institutional Review Board and the IACUC committee.

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Supplementary information

Supplementary Tables and Figure Legends

41391_2022_590_MOESM2_ESM.png

Supplemental Figure 1: Immunohistochemical staining of prostate cancer adrenal metastases for androgen receptor (AR), glucocorticoid receptor (GR), and NKX3.1.

41391_2022_590_MOESM3_ESM.png

Supplemental Figure 2: Organoids developed from MDA-PCa-250 can convert adrenal androgens and progesterone to testosterone

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Sakellakis, M.J., Hahn, A.W., Ramachandran, S. et al. Characterization of prostate cancer adrenal metastases: dependence upon androgen receptor signaling and steroid hormones. Prostate Cancer Prostatic Dis 26, 751–758 (2023). https://doi.org/10.1038/s41391-022-00590-x

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