Yingbo GUO

Research team

Cancer, Metabolism and Environment

Role of the primary cilium in neuroendocrine transdifferentiation of prostate cancer

Abstract :

Prostate cancer is one of the most common malignancy cancers worldwide. 95% of PCa patients are diagnosed with adenocarcinoma of the prostate showing no expression of neuroendocrine markers. De novo neuroendocrine prostate cancer is a rare and aggressive subtype of prostate cancer, characterized by neuroendocrine markers expression. Approximatively 20% of adenocarcinoma cases progress to neuroendocrine prostate cancer following androgen deprivation therapy. The potential side effect of androgen deprivation therapy, resulting in neuroendocrine differentiation of adenocarcinoma of the prostate, brings a novel challenge for prostate cancer treatment. While many molecular mechanisms of neuroendocrine differentiation have been described, the timing of the neuroendocrine differentiation occurrence and how these driving factors result in neuroendocrine differentiation remain unclear.

The primary cilium is a non-motile organelle present in nearly all human cells. Loss of primary cilium has been observed in various cancers, including clear cell Renal Cell Carcinoma (ccRCC) and PCa. Previous findings from our research team identified a distinct subgroup of patients within ccRCC, which retained primary cilium and exhibited resistance to therapy. The presence of primary cilium was characterized by the GLI1+/IFT20+signature. Under hypoxic conditions, primary cilium was inhibited due to stabilization of HIF-1α, correlating with increased aggressiveness of ccRCC. Considering that both ccRCC and prostate cancer are typically described as cancer lacking PC, we postulated the existence of a unique subgroup in prostate cancer exhibiting primary cilium presence associated with higher aggressiveness.

We developed multiple approaches to enhance in the number of primary cilium numbers in both normal prostate cells and prostate cancer-like cells in 2D or 3D cell culture settings. This increase was correlated with a reduction in proliferation and growth of 3D structures. Notably, these methods maintained their effectiveness in inducing primary cilium numbers even under hypoxic conditions. Our findings confirmed the robustness of the GLI1+/IFT20+ signature in increasing primary cilium numbers in normal cells, while this signature was less pronounced in prostate cancer-like cells. In parallel, we discovered that the restoration of primary cilium in prostate cancer cells is associated to the neuroendocrine transdifferentiation of prostate cancer. Furthermore, the regulation of primary cilium is linked to the cancer aggressiveness.

Our research provides evidence that primary cilium is present in a more aggressive subgroup of prostate cancer patients, similar to what is observed in ccRCC. Analyzing the role of primary cilium in the transdifferentiation of prostate cancer provides new insights into potential treatment strategies.

Keywords : 

Prostate cancer; Primary cilium; Neuroendocrine transdifferentiation; YAP1; Hypoxia