Primary Cilia Drive Neuroendocrine Shift in Prostate Cancer by Repressing YAP1 and Reducing Mitochondrial Activity

Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer (PCa) that frequently emerges following androgen receptor (AR)-targeted therapies for castration-resistant prostate cancer (CRPC). This shift, known as neuroendocrine differentiation (NED), represents a significant clinical challenge due to its poor prognosis and limited treatment options. Understanding the molecular drivers of NED is crucial for identifying new therapeutic vulnerabilities and biomarkers. Primary cilia, once considered vestigial, are now recognized as key regulators of cellular signaling and plasticity, making them a compelling area of study in this context.

Researchers investigated the distribution and role of primary cilia in neuroendocrine prostate cancer using both in vitro models and patient samples. They examined neuroendocrine-like cells and CRPC samples for cilium presence and correlated it with FDG-PET positivity and neuroendocrine features in vivo. Mitochondrial activity was assessed to understand metabolic reprogramming. Building on prior work, they identified a GLI1⁺/IFT20⁺ or GLI1⁺/IFT80⁺ signature in ciliated, NE-prone subpopulations. They also tested the effects of YAP1 inhibition and cytoskeletal remodeling with jasplakinolide on cilium assembly and NE transdifferentiation. Single-cell RNA-seq analyses were performed to identify gene enrichment patterns.

Primary cilia, typically absent in localized hormone-sensitive prostate tumor cells, were consistently detected in neuroendocrine-like cells in vitro and in CRPC patient samples. In vivo, cilia were observed in CRPC tumor cells exhibiting FDG-PET positivity and neuroendocrine features, strongly supporting an association between ciliogenesis, metabolic reprogramming, and disease progression. These aggressive tumors also displayed reduced mitochondrial activity, consistent with a shift away from oxidative metabolism. A GLI1⁺/IFT20⁺ or GLI1⁺/IFT80⁺ signature was enriched in ciliated, NE-prone subpopulations. While YAP1 inhibition alone did not induce ciliogenesis, cytoskeletal remodeling with jasplakinolide restored cilium assembly and enabled partial neuroendocrine transdifferentiation. Single-cell RNA-seq analyses further showed significant enrichment of ciliogenesis-related genes within neuroendocrine clusters in CRPC.

These observations support a model where primary cilia are closely associated with neuroendocrine identity and metabolic adaptation, acting as active drivers rather than passive markers.