Mathematical insights into neuroendocrine transdifferentiation of human prostate cancer cells

Prostate cancer represents the second most common cancer diagnosed in men and the fifth most common cause of death from cancer worldwide. In this paper, we consider a nonlinear mathematical model exploring the role of neuroendocrine transdifferentiation in human prostate cancer cell dynamics. Sufficient conditions are given for both the biological relevance of the model’s solutions and for the existence of its equilibria. By means of a suitable Liapunov functional the global asymptotic stability of the tumour-free equilibrium is proven, and through the use of sensitivity and bifurcation analyses we identify the parameters responsible for the occurrence of Hopf and saddle-node bifurcations. Numerical simulations are provided highlighting the behaviour discovered, and the results are discussed together with possible improvements to the model.

PCa dynamics with neuroendocrine differentiation and distributed delay

<abstract><p>Prostate cancer is the fifth most common cause of death from cancer, and the second most common diagnosed cancer in men. In the last few years many mathematical models have been proposed to describe the dynamics of prostate cancer under treatment. So far one of the major challenges has been the development of mathematical models that would represent <italic>in vivo</italic> conditions and therefore be suitable for clinical applications, while being mathematically treatable. In this paper, we take a step in this direction, by proposing a nonlinear distributed-delay dynamical system that explores neuroendocrine transdifferentiation in human prostate cancer <italic>in vivo</italic>. Sufficient conditions for the existence and the stability of a tumour-present equilibrium are given, and the occurrence of a Hopf bifurcation is proven for a uniform delay distribution. Numerical simulations are provided to explore differences in behaviour for uniform and exponential delay distributions. The results suggest that the choice of the delay distribution is key in defining the dynamics of the system and in determining the conditions for the onset of oscillations following a switch in the stability of the tumour-present equilibrium.</p></abstract>

Single-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

Single-cell analysis supports a luminal-neuroendocrine trans-differentiation in human prostate cancer

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore novel intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma

Neuroendocrine prostate cancer (NEPC) can arise de novo, but much more commonly occurs as a consequence of a selective pressure from androgen deprivation therapy or androgen receptor antagonists used for prostate cancer (PCa) treatment. The process is known as neuroendocrine transdifferentiation. There is little molecular characterization of NEPCs and consequently there is no standard treatment for this kind of tumors, characterized by highly metastases rates and poor survival. For this purpose, we profiled 54 PCa samples with more than 10-years follow-up for gene and miRNA expression. We divided samples into two groups (NE-like vs. AdenoPCa), according to their clinical and molecular features. NE-like tumors were characterized by a neuroendocrine fingerprint made of known neuroendocrine markers and novel molecules, including long non-coding RNAs and components of the estrogen receptor signaling. A gene expression signature able to predict NEPC was built and tested on independently published datasets. This study identified molecular features (protein-coding, long non-coding, and microRNAs), at the time of surgery, that may anticipate the NE transformation process of prostate adenocarcinoma. Our results may contribute to improving the diagnosis and treatment of this subgroup of tumors for which traditional therapy regimens do not show beneficial effects.