Adipokine Hormone Axes: Uncovering A Critical Role in Advanced Prostate Cancer Progression

Resistance to mainstay treatments underlies incurable disease in advanced metastatic prostate cancer (PCa). Androgen-targeted therapies (ATTs) are initially efficacious, starving PCa of growth-promoting androgens. However, tumours inevitably recur, adapting to treatment via various mechanisms including ATT-induced lineage plasticity. Furthermore, ATT use induces patient metabolic dysfunction, seen in raised blood lipids, glucose and insulin, and dysregulation of the circulating adipose tissue-secreted hormone (adipokine) milieu, all of which contribute to more aggressive disease. We uncovered adipokine hormone receptors are too altered in PCa cells and patient tumours exposed to ATTs, and their dysregulation correlates with poor outcome, metastases and treatment resistance in patients. Adipokine signalling axes exhibit major crossovers with several cancer-promoting hallmark pathways, including invasion, migration, proliferation, survival, angiogenesis, inflammation and metabolism. We hypothesised that targeting the dysregulation of key adipokines presents an attractive novel therapeutic modality, especially in advanced PCa where current treatments fail. This study explored dysregulation of the adipokine axes in relation to adaptive tumour cell plasticity and treatment resistance using cell and xenograft models, and public patient transcriptomic analyses. Dysregulated adipokine hormone axes strongly associated with markers of tumour cell plasticity and metastasis in PCa. Adipokine-targeted therapies suppressed subcutaneous tumour progression in vivo, increasing doubling time and delaying time to castration resistance, vs vehicle; subsequent transcriptomic analyses of tumours highlighted altered pathways of cell adherence and epithelial junction remodelling. Future preclinical testing of adipokine-targeted therapies in further models of metastasis will build proof-of-principle to uncover a promising new therapeutic strategy, vital in the management of advanced PCa.