Anti-androgen therapy induces transcriptomic reprogramming in metastatic castration-resistant prostate cancer in a murine model

Biochim Biophys Acta Mol Basis Dis. 2021 Jul 1;1867(7):166151. doi: 10.1016/j.bbadis.2021.166151. Epub 2021 Apr 21.

Abstract

Despite recent development of next-generation androgen receptor (AR) antagonists, metastatic castration-resistant prostate cancer (CRPC) remains incurable and requires deeper understanding through studies in suitable animal models. Prostate-specific deletion of Pten and Smad4 in mice recapitulated the disease progression of human prostate adenocarcinoma, including metastasis to lymph nodes and lung. Moreover, Pten/Smad4 tumors fostered an immunosuppressive microenvironment dominated by myeloid-derived suppressor cells (MDSCs). However, the response of Pten/Smad4 tumors to androgen deprivation and anti-androgen therapies has not been described. Here, we report that the combination of surgical castration and enzalutamide treatment in Pten/Smad4 mice slowed down the tumor growth and prolonged the median survival of the mice for 8 weeks. Treatment-naïve and castration-resistant primary tumors exhibited comparable levels of immune infiltrations with the exception of reduced monocytic MDSCs in CRPC. RNA profiling of treatment-naïve and castration-resistant primary tumors revealed largely preserved transcriptome with modest expressional alterations of collagen-related and immune-related genes, among which CC chemokine receptor type 2 (Ccr2) downregulation and predicted negative activation in CRPC was consistent with reduced monocytic MDSC infiltration. Importantly, significant transcriptomic reprograming was observed in lung metastatic CRPC compared with primary CRPC and enriched for immune-related and coagulation-related pathways. At the individual gene level, we validated the expression changes of some of the most upregulated (Cd36, Bmp5, Bmp6, Etv5, Prex2, Ptprb, Egfl6, Itga8 and Cxcl12) and downregulated genes (Cxcl9 and Adamts5). Together, this study uncovers the inherent activity of Pten/Smad4 tumors to progress to CRPC and highlights potentially targetable transcriptomic signatures associated with CRPC metastasis.

Keywords: Castration-resistant prostate cancer; Genetically engineered mouse model; Lung metastasis; Myeloid-derived suppressor cell; Pten; Smad4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Animals
  • Apoptosis
  • Cell Proliferation
  • Disease Models, Animal*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Male
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase / physiology
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Smad4 Protein / physiology
  • Transcriptome / drug effects*
  • Tumor Cells, Cultured

Substances

  • Androgen Antagonists
  • Smad4 Protein
  • Smad4 protein, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse