Identifying and characterizing gene co-expression modules underlying resistance to Androgen deprivation therapy in prostate cancer

Most men with prostate adenocarcinoma are initially diagnosed with disease confined to the prostate, where it is typically treated with surgery and/or radiotherapy. While these approaches are often curative, some tumours persist or recur, requiring androgen deprivation therapy (ADT). Over time, many cancers adapt to survive in low-androgen conditions and progress to a more aggressive, treatment-resistant state known as castrate-resistant prostate cancer (CRPC). CRPC is frequently lethal, highlighting the urgent need to better understand the mechanisms by which prostate cancer progresses and evades therapy.

Australian Rotary Health and the Rotary Club of Williamstown’s ‘Rotary Ride for a Cure’ Ronnie Goldberg PhD Scholarship recipient, Mikhail Dias, investigates prostate cancer from an evolutionary perspective. The research focuses on the emergence of multicellular life, which developed the ability for cells to cooperate within tissues. Healthy tissues depend on specialized gene regulatory networks (GRNs) that enable communication and coordination among cells. In cancer, these GRNs break down, driving cells toward more primitive, unicellular-like behaviors, characterized by unchecked growth and survival.

To investigate this process, the Evolutionary Network Analysis (ENA) pipeline was developed, which tracks changes in GRNs across prostate cancer progression, from localized disease to advanced, drug-resistant tumours. Analysis revealed that as tumours become more aggressive, the networks that maintain multicellularity are progressively rewired. This rewiring facilitates the reactivation of ancient unicellular programs, driving uncontrolled growth, altered metabolism, and resistance to therapy.

Importantly, these network changes continue as cancer spreads and becomes resistant to hormone therapy. By mapping these shifts, research identified potential vulnerabilities within the cancer’s regulatory system that could be targeted for new treatments.

Findings provide a novel framework for understanding prostate cancer progression and resistance. By focusing on the breakdown of multicellular cooperation, this approach may help guide the development of more effective therapies for men with advanced disease.

Media contact: [email protected]       First published 30th September 2025

Graphic acknowledgement: FreePik.com