Abstract
Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model, we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem/progenitor cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks' level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.
Highlights
48 49 Stem cells exhibit plasticity as the state of stemness is modulated by various intrinsic and extrinsic factors (Magee, Piskounova et al, 2012)(Folmes, Dzeja et al, 2012)
The HaCaT cells carry non-functional p53 (St John, Sauter et al, 2000), which provides the appropriate cellular context given Drp[1] inactivation increases cell proliferation in the absence of active p53 (Mitra, Rikhy et al, 2012, Mitra, Wunder et al, 2009). We used both mild and strong dose of TCDD to uncover any possibility of mitochondria based priming of stemness during TCDD driven neoplastic transformation
TCDD driven carcinogenesis is caused by activation and upregulation of the aryl hydrocarbon receptor (AHR)
Summary
48 49 Stem cells exhibit plasticity as the state of stemness is modulated by various intrinsic and extrinsic factors (Magee, Piskounova et al, 2012)(Folmes, Dzeja et al, 2012). Drp[1] activation sustains neoplastic stem cells at least in the astrocytic lineage (Xie et al, 2015), and genetic ablation of Drp[1] prevents neoplastic transformation (Serasinghe et al, 2015). An elevated mitochondrial fusion state, sustained by mitofusin, can drive immortalization of neoplastic stem cells to support tumorigenesis in a Drosophila model (Bonnay, Veloso et al, 2020). We found that select neoplastic ovarian epithelial stem cells (marked by Aldh) have lower levels of mitochondrial fission and can convert to a state of elevated mitochondrial fission when self-renewal and proliferation is activated. We proposed, that a repressed mitochondrial fission state may prime neoplastic stem cells towards maximizing their potential of selfrenewal and proliferation. We established a transformed skin keratinocyte model that sustains abundant self-renewing/proliferating cells with attenuated Drp[1] activity. Our data for the first time highlights a ‘goldilocks’ level of Drp[1] repression that supports stem/progenitor-like state dependent neoplastic transformation
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