A MicroRNA Promotes Neuroendocrine Transdifferentiation in Prostate Cancer

Researchers have identified a new mechanism in which prostate cancer cells can 'switch' character and become resistant to therapy.

These findings, just published in Cell Reports, are an important development in unravelling how an aggressive subtype of prostate cancer, neuroendocrine prostate cancer (NEPC), develops after hormonal therapies.

It is well established that some tumours show increased cellular 'plasticity' in response to new or stressful conditions, such as cancer therapy, says lead researcher.

This plasticity allows the cancer cells to adapt and continue to grow by evolving into different cell types that no longer respond to the therapy.

"Increased cellular plasticity is increasingly recognised as a key feature by which prostate cancers become resistant to therapy and progress to a lethal stage," the author says.

"Our new study reveals that a particular molecule, the microRNA 'miR-194', can enhance this plasticity in prostate cancer, leading to the emergence of NEPC.

In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity.

One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features.

"By targeting miR-194, we were able to slow down and inhibit the growth of prostate cancer models with neuroendocrine features."

The author says while this study is a long way from clinical application, it "nevertheless provides us with important new insights into how prostate cancers 'evolve' in response to therapy".

There are currently no effective treatments for NEPC, with estimates up to 15% of men may develop this aggressive subtype of prostate cancer after hormonal treatment - a major problem because these men face "very poor outcomes".

"By revealing another regulator of prostate cancer cell plasticity that can promote evolution of tumours, our study highlights why prostate cancer is so difficult to cure.

"While this reality is sobering, we hope that our study and lots of other research going on around the world will eventually lead to smarter, more targeted ways to treat NEPC or even prevent its emergence," the author says.

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31574-6

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