MALAT1 Fusions and Basal Cells Contribute to Primary Resistance against Androgen Receptor Inhibition in TRAMP Mice

Maximilian Marhold; Simon Udovica; Thais Topakian; Peter Horak; Reinhard Horvat; Erwin Tomasich; Gerwin Heller; Michael Krainer

doi:10.3390/cancers14030749

MALAT1 Fusions and Basal Cells Contribute to Primary Resistance against Androgen Receptor Inhibition in TRAMP Mice

Cancers (Basel). 2022 Jan 31;14(3):749. doi: 10.3390/cancers14030749.

Authors

Maximilian Marhold^{1

2}, Simon Udovica³, Thais Topakian^{1

2}, Peter Horak⁴, Reinhard Horvat⁵, Erwin Tomasich^{1

2}, Gerwin Heller^{1

2}, Michael Krainer^{1

2}

Affiliations

¹ Division of Oncology, Department for Medicine I, Medical University of Vienna, A-1090 Vienna, Austria.
² Comprehensive Cancer Center Vienna, Medical University of Vienna, A-1090 Vienna, Austria.
³ Clinic of Internal Medicine I and Wilhelminen Cancer Research Institute, Klinik Ottakring, A-1090 Vienna, Austria.
⁴ National Tumor Center (NCT), DKFZ, 69120 Heidelberg, Germany.
⁵ Institute for Pathology, Medical University of Vienna, A-1090 Vienna, Austria.

Abstract

Targeting testosterone signaling through androgen deprivation therapy (ADT) or antiandrogen treatment is the standard of care for advanced prostate cancer (PCa). Although the large majority of patients initially respond to ADT and/or androgen receptor (AR) blockade, most patients suffering from advanced PCa will experience disease progression. We sought to investigate drivers of primary resistance against antiandrogen treatment in the TRAMP mouse model, an SV-40 t-antigen driven model exhibiting aggressive variants of prostate cancer, castration resistance, and neuroendocrine differentiation upon antihormonal treatment. We isolated primary tumor cell suspensions from adult male TRAMP mice and subjected them to organoid culture. Basal and non-basal cell populations were characterized by RNA sequencing, Western blotting, and quantitative real-time PCR. Furthermore, effects of androgen withdrawal and enzalutamide treatment were studied. Basal and luminal TRAMP cells exhibited distinct molecular signatures and gave rise to organoids with distinct phenotypes. TRAMP cells exhibited primary resistance against antiandrogen treatment. This was more pronounced in basal cell-derived TRAMP organoids when compared to luminal cell-derived organoids. Furthermore, we found MALAT1 gene fusions to be drivers of antiandrogen resistance in TRAMP mice through regulation of AR. Summarizing, TRAMP tumor cells exhibited primary resistance towards androgen inhibition enhanced through basal cell function and MALAT1 gene fusions.

Keywords: MALAT1; TRAMP mouse; androgen receptor inhibition; enzalutamide; prostate cancer.