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BNIP3 IN MELANOMA: SITTING ON THE IRON THRONE Unraveling the role of BNIP3 in mitochondrial homeostasis, metabolism and melanoma growth

Boek - Dissertatie

Melanoma is the deadliest form of skin cancer due to its ability to metastasize rapidly and to become resistant to various forms of therapies. To support their aggressive phenotype, melanoma cells require metabolic plasticity, which they acquire by hijacking key adaptive responses like the hypoxia-inducible response and autophagy. On the one hand, abnormal stabilization and upregulation of Hypoxia Inducible Factor 1 alpha (HIF-1α) have been associated with a higher glycolytic capacity and poorer prognosis in melanoma. On the other hand, autophagy has been shown to play a dual role in melanoma. By operating as a vital quality control mechanism, autophagy prevents first the malignant transformation of melanocytes. However, autophagy supports melanoma progression at the later stages, by enhancing its adaptation to the metabolically stressed tumor microenvironment. Moreover, a specialized form of autophagy called mitophagy ensures the selective removal of damaged or dysfunctional mitochondria to maintain a healthy mitochondrial network. A healthy mitochondrial network is decisive for the maintenance of metabolic and bio-energetic homeostasis as well as cell death regulation. Although the molecular underpinnings of mitophagy regulation in mammalian cells remain incomplete, it is becoming clear that the mitophagy pathways are intricately linked to the metabolic rewiring of cancer cells, including melanoma, to support the high bio-energetic demands of the tumor. Interestingly, the BH3-only protein BCL2/adenovirus E1B 19kDa protein-interacting protein 3 (BNIP3) resides at the intersection between hypoxia signaling and mitochondrial homeostasis since BNIP3 is both a bona fide HIF-1α target and a mitophagy receptor. Depending on the cancer type, BNIP3 has been described to play either a tumor promoter or a tumor suppressor role, but an in-depth understanding of the molecular mechanisms enabling BNIP3 to control tumor growth is still missing. In the particular case of melanoma, previous studies of the lab have shown that BNIP3 confers a survival advantage to melanoma cells in vitro; yet, its role in vivo and how it affected melanoma cell's metabolism remained unexplored. Therefore, the goal of this doctoral thesis was to understand whether melanoma cells become addicted to a BNIP3-regulated axis to maintain a metabolically plastic phenotype, how this axis would promote tumor growth and the extent to which HIF-1α signaling and autophagy contributed to this behavior. The present thesis addresses the complex role of BNIP3 in melanoma on different levels: through the analysis of patient material and of a syngeneic melanoma mouse model as well as through an in-depth mechanistic study, whereby possible BNIP3-specific functions were discriminated against from those of a canonical autophagy gene (autophagy related 5, ATG5). Transcriptomic and immunohistochemical (IHC) analysis of melanoma patient samples showed that higher BNIP3 levels correlated with poorer prognosis. Furthermore, BNIP3 protein levels were found elevated in primary melanoma and further heightened in metastatic samples. Silencing BNIP3 in murine melanoma cells curbed their ability to grow once transplanted in vivo to a more severe extent than compromising melanoma cell-autophagy alone. In fact, both in vivo and in vitro studies revealed that BNIP3 fostered melanoma growth by maintaining elevated cellular HIF-1α levels as well as its glycolytic and pro-angiogenic program. Mechanistically, the absence of BNIP3 impaired mitophagy, altered the metabolic profile of melanoma cells and unbalanced cellular iron homeostasis. By stimulating ferritinophagy, BNIP3 silencing increased in the intracellular labile iron pool, which further supported prolyl hydroxylase domain-containing protein 2 (PHD2)-mediated downregulation of HIF-1α. Altogether, these data unraveled an unprecedented feedforward loop between BNIP3- HIF-1α that supports melanoma progression. Overall, this doctoral thesis reveals novel mechanisms through which BNIP3 supports melanoma cell metabolism and aggressiveness, thereby endorsing BNIP3 as a tumor promoter in melanoma. Upon further exploration, these mechanisms may thus provide new therapeutic opportunities for melanoma patients in the near future.
Jaar van publicatie:2021
Toegankelijkheid:Open