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Neuroendocrine Transdifferentiation in Human Prostate Cancer Cells: An Integrated Approach
Marianna Cerasuolo1, Debora Paris2, Fabio A Iannotti2
1University of Portsmouth, Department of Mathematics, Hampshire, United Kingdom.
Abstract:
Prostate cancer is highly sensitive to hormone therapy because androgens are essential for prostate cancer cell growth. However, with the nearly invariable progression of this disease to androgen independence, endocrine therapy ultimately fails to control prostate cancer in most patients. Androgen-independent acquisition may involve neuroendocrine transdifferentiation, but there is little knowledge about this process, which is presently controversial. In this study, we investigated this question in a novel model of human androgen-dependent LNCaP cells cultured for long periods in hormone-deprived conditions. Strikingly, characterization of the neuroendocrine phenotype by transcriptomic, metabolomic, and other statistically integrated analyses showed how hormone-deprived LNCaP cells could transdifferentiate to a nonmalignantneuroendocrine phenotype. Notably, conditioned media from neuroendocrine-like cells affected LNCaP cell proliferation. Predictive in silico models illustrated how after an initial period, when LNCaP cell survival was compromised by an arising population of neuroendocrine-like cells, a sudden trend reversal occurred in which the neuroendocrine-like cells functioned to sustain the remaining androgen-dependent LNCaP cells. Our findings provide direct biologic and molecular support for the concept that neuroendocrine transdifferentiation in prostate cancer cell populations influences the progression to androgen independence.
Insights
Prostate cancer cells can change into a neuroendocrine type when deprived of hormones. These new cells initially hinder, then surprisingly support, the growth of remaining cancer cells, driving androgen independence.
Area of Science:
- Oncology
- Cell Biology
- Endocrinology
Background:
- Prostate cancer initially responds to hormone therapy due to androgen dependence.
- Progression to androgen independence leads to treatment failure.
- Neuroendocrine transdifferentiation is a proposed but poorly understood mechanism for this progression.
Purpose of the Study:
- To investigate neuroendocrine transdifferentiation in prostate cancer using a novel cell model.
- To characterize the molecular and phenotypic changes during this process.
- To understand the role of neuroendocrine cells in prostate cancer progression.
Main Methods:
- Long-term culture of human androgen-dependent LNCaP cells in hormone-deprived conditions.
- Transcriptomic and metabolomic analyses to characterize the neuroendocrine phenotype.
- Co-culture experiments and in silico modeling to assess cell interactions and predict outcomes.
Main Results:
- Hormone-deprived LNCaP cells successfully transdifferentiated into a non-malignant neuroendocrine phenotype.
- Conditioned media from neuroendocrine-like cells influenced the proliferation of LNCaP cells.
- In silico models revealed a biphasic effect: initial compromise followed by support of androgen-dependent cells by neuroendocrine-like cells.
Conclusions:
- Direct biological and molecular evidence supports neuroendocrine transdifferentiation in prostate cancer.
- This transdifferentiation process plays a significant role in the development of androgen independence.
- Understanding this mechanism may offer new therapeutic strategies for advanced prostate cancer.
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