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Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance
Mannan Nouri1,2, Josselin Caradec1,2, Amy Anne Lubik1,2
1Vancouver Prostate Centre, Vancouver, Canada.
Abstract:
Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.
Insights
Prostate cancer cells can reprogram into neural stem-like cells, driving therapeutic resistance and metastasis. This reprogramming cycle may explain aggressive disease and suggests new therapeutic targets for advanced prostate cancer (PCa).
Area of Science:
- Cancer Biology
- Prostate Cancer Research
- Stem Cell Biology
Background:
- Treatment-induced neuroendocrine transdifferentiation (NEtD) is a challenge in metastatic prostate cancer (PCa) therapy.
- Prostate cancer cells exhibit plasticity, with potential for transdifferentiation into neuroectodermal lineages.
- A proposed model suggests NEtD involves an intermediate stage of metastable neural cancer stem-like cells (CSCs).
Purpose of the Study:
- To investigate the role of intermediate neural CSCs in prostate cancer reprogramming and therapeutic resistance.
- To characterize the properties of PCa cells reprogrammed into CSCs.
- To identify potential biomarkers associated with aggressive PCa outcomes.
Main Methods:
- Reprogramming of AR+/PSA+ PCa cell lines into CSCs using androgen-free neural/neural crest (N/NC) stem medium.
- Characterization of reprogrammed cells for differentiation markers, stem cell features, tumor-initiating potential, and invasiveness.
- Assessment of resistance to androgen signaling inhibition and re-differentiation capabilities.
- Analysis of a 132-gene signature in patient tumors to correlate with clinical outcomes.
Main Results:
- PCa cell lines were successfully reprogrammed into N/NC-like CSCs, losing prostate differentiation markers and gaining stem cell and tumor-initiating properties.
- Reprogrammed CSCs exhibited resistance to androgen signaling inhibition and acquired invasive phenotypes in vitro and in vivo.
- Reprogrammed cells could be re-differentiated to neural lineages or revert to a resistant AR+ prostate-like state.
- A 132-gene signature from reprogrammed cells identified PCa tumors associated with adverse outcomes, including metastasis and mortality.
Conclusions:
- Prostate cancer cells can undergo metastable reprogramming to neural stem-like cells, contributing to therapeutic resistance and aggressive phenotypes.
- Cycles of reprogramming and re-differentiation may drive disease progression and treatment failure in advanced PCa.
- The identified gene signature highlights the link between developmental reprogramming and lethal prostate cancer, offering potential diagnostic and therapeutic insights.
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