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bioRxiv · 10.1101/2021.11.10.468020

Mitochondrial calcium uptake regulates tumour progression in embryonal rhabdomyosarcoma

Taneja, R.·Chiu, H. Y.·Loh, A. H. P.
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Abstract

Embryonal rhabdomyosarcoma (ERMS) is characterized by a failure of cells to complete skeletal muscle differentiation. Although ERMS cells are vulnerable to oxidative stress, the relevance of mitochondrial calcium homeostasis in oncogenesis is unclear. Here, we show that ERMS cell lines as well as primary tumours exhibit elevated expression of the Mitochondrial Calcium Uniporter (MCU). MCU knockdown resulted in impaired mitochondrial calcium uptake and a reduction in mitochondrial reactive oxygen species (mROS) levels. Phenotypically, MCU knockdown cells exhibited reduced cellular proliferation and motility, with an increased propensity to differentiate in vitro and in vivo. RNA-sequencing of MCU knockdown cells revealed a significant reduction in genes involved in TGF{beta} signalling that play prominent roles in oncogenesis and inhibition of myogenic differentiation. Interestingly, modulation of mROS production impacted TGF{beta} signalling. Our study elucidates mechanisms by which mitochondrial calcium dysregulation promotes tumour progression and suggests that targeting the MCU complex to restore mitochondrial calcium homeostasis could be a therapeutic avenue in ERMS.

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Taneja, R., Chiu, H. Y., Loh, A. H. P.. 2021-11-10. Mitochondrial calcium uptake regulates tumour progression in embryonal rhabdomyosarcoma. https://doi.org/10.1101/2021.11.10.468020

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