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Transcriptional mediators of treatment resistance in lethal prostate cancer.

ABSTRACT: Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors¹. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies^2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. ^4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8⁺ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.

SUBMITTER: He MX

PROVIDER: S-EPMC7960507 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Transcriptional mediators of treatment resistance in lethal prostate cancer.

He Meng Xiao MX Cuoco Michael S MS Crowdis Jett J Bosma-Moody Alice A Zhang Zhenwei Z Bi Kevin K Kanodia Abhay A Su Mei-Ju MJ Ku Sheng-Yu SY Garcia Maria Mica MM Sweet Amalia R AR Rodman Christopher C DelloStritto Laura L Silver Rebecca R Steinharter John J Shah Parin P Izar Benjamin B Walk Nathan C NC Burke Kelly P KP Bakouny Ziad Z Tewari Alok K AK Liu David D Camp Sabrina Y SY Vokes Natalie I NI Salari Keyan K Park Jihye J Vigneau Sébastien S Fong Lawrence L Russo Joshua W JW Yuan Xin X Balk Steven P SP Beltran Himisha H Rozenblatt-Rosen Orit O Regev Aviv A Rotem Asaf A Taplin Mary-Ellen ME Van Allen Eliezer M EM

Nature medicine 20210304 3

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors<sup>1</sup>. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma c ...[more]

PMID: 33664492

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Project description:BACKGROUND: Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined. METHODOLOGY/PRINCIPAL FINDINGS: Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth. CONCLUSIONS: Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways.

Dataset Information

Transcriptional mediators of treatment resistance in lethal prostate cancer.

Publications

Transcriptional mediators of treatment resistance in lethal prostate cancer.

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