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

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.

Single-cell RNA sequencing reveals intratumoral heterogeneity and potential mechanisms of malignant progression in prostate cancer with perineural invasion

“…In a recent study, the basal cell gene-expression profile was found to be significantly enriched in castration-resistant and advanced prostate cancers ( Zhang et al, 2016 ), which indicated basal cells might play a potential role in the development of resistance to anti-androgens in PCa. In a study published by Marhold et al showed that basal cells were involved in primary resistance to androgen receptor inhibition in the TRAMP mouse model ( Marhold et al, 2022 ). In addition, increasing evidence suggested that androgen signaling through the androgen receptor ( AR ) contributes to the promotion of castration-resistant prostate cancer ( CR PC) ( Zhou et al, 2017 ).…”

Cancer fusion transcripts with human non-coding RNAs

“…For example, MALAT1 can regulate expression of the androgen receptor and thereby controls proliferation, invasion, and migration of prostate cancer cells. In addition, MALAT1 is believed to downregulate specific types of splicing in patients with metastatic Castrate-resistant prostate cancer ( 128 – 130 ). MALAT1 is overexpressed and used as a prognostic biomarker in various cancer types including lung, breast, liver, pancreas, renal, colon, bladder, uterus, and cervix cancers ( 131 , 132 ).…”

“…MALAT1-MVP and MALAT1-NCBP3: In a prostate cancer mouse model, MALAT1 fusions, including MALAT1-MVP and MALAT1-NCBP3, were found to be implicated in resistance to second-generation antiandrogen cancer drugs ( 130 ). Notably, the fusion partner NCBP3 (Nuclear Cap-Binding Protein 3) is associated with nuclear–cytoplasmic transport ( 136 ), and MVP (major vault protein) is related to multidrug resistance in various malignancies ( 137 ).…”