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UBC Theses and Dissertations

Sox9 mediated reprogramming of prostate cancer cells and acquired therapy resistance Nouri, Mannan


Treatment-induced neuroendocrine trans-differentiation (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 transition medium (STM). Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells including tumour-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. These aggressive features were linked to overexpression of N/NC master regulator Sox9, with concomitant loss of Rb1 and p53 function. Functional analysis employing Sox9 constructs phenocopied invasive and expression profiles of STM-mediated development reprogramming. Meanwhile, targeting of Sox9 and it’s upstream activators reduced aggressive features and sensitized cells to androgen signalling inhibition. Acute androgen deprivation or anti-androgen treatment of PCa cells led to the transient appearance of a sub-population of cells with similar characteristics to the developmentally reprogrammed CSCs described above. Notably, a 132-gene signature derived from reprogrammed PCa cell lines distinguished tumours from PCa patients with adverse outcomes. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or re-differentiate to an AR⁺ prostate-like state. Once returned, the AR⁺ cells were resistant to androgen signaling inhibition, and had retained aggressiveness markers like NRP1 and EZH2 associated with the CSC state. 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 tumours from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumour behaviors. Finally, the signature of serum return cells functioned as a recurrence model in identifying genes associated with enhanced aggressiveness in therapy resistance.

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