Research Projects

Breast cancer (BC) metastasis stages immense mortality globally as well as in india it is expected to rise by 61.7% in the next decade. Traditional treatment modalities for have failed due to non-specific drug targeting to the tumor tissue and drug resistance. Mitochondrial regulation of cellular metabolism via dynamics alteration in mitochondrial fusion-fission and key cell death pathways imparts a critical role in tumorigenesis and anti-tumoral response in cancer context specificity. From this perspective, targeting mitochondrial genes has evolved as a compelling method for inhibition of BC. Recent studies have highlighted the role of mitochondrial dynamics in malignant transformation of BC, glycolytic shift, mitochondrial biogenesis, and subsequent manipulation of cell death pathways for survival. The key mitochondrial fission regulator protein DNM1L as associated with signalling genes, has been found to be upregulated in BC metastatic cells. Preliminary evidence has suggested that apart from regulating the mitochondrial dynamics, MTP18 influences spatio-temporal recruitment of DNM1L to the mitochondrial fission site, which is essential for mitochondrial bioenergetics, metabolic reprogramming and refraining apoptotic cell death pathways. However, the molecular mechanisms underlying such peculiar phenomena have not been investigated. Previously, we have investigated that mitochondrial fission requires outer-membrane constriction by DNM1L along with a key transmembrane protein MTP18 that reciprocates inner-membrane constriction. This proposal aims to investigate the regulatory role of Mitochondrial Transmembrane Protein 18 (MTP18); a nuclear-encoded mitochondrial inner membrane protein in BC metastasis via regulating mitochondrial dynamics, structural integrity, and metabolic reprogramming. Hence, inhibition of MTP18 will onset apoptotic cell death signalling for subsequent inhibition of BC metastasis by identifying a novel phytochemical. Mechanistically, the proposal aims to investigate the MTP18-DNM1L signalling nexus during progressive stages of BC metastasis with a focus on mitochondrial fission, mitochondrial biogenesis, mitophagy, and mitochondrial metabolism, and further screen out a novel phytochemical as an MTP18 inhibitor, used as a therapeutic in BC metastasis. Using in vitro model (MCF-7,4T1and MDA-MB-231cells), we will assess the critical role of MTP18-DNM1L signalling in the regulation of mitochondrial dynamics and metabolic reprogramming that aids BC metastasis. We will also examine how the novel identified phytochemical, as an MTP18 inhibitor, regulates the mitochondrial morphology and affects invasion and metastasis of BC via altering the mitochondrial metabolism and confronting apoptotic cell death pathways. Further, the pre-clinical efficacy of the MTP18 inhibitor will be assessed in vivo (BALB/c xenograft) mice models. The tumor slides will be processed for key mitochondrial dynamics-associated protein expression analysis.