Research Projects

Rationale of research: Unfortunately, regardless of technical advancements, India is world capital of oral cancer. Oral-tumor growth aggressiveness, therapeutic resistance and recurrence is driven by a self-eating metabolic phenomenon called autophagy. During autophagy a cell undergoing stress like therapy, low nutrient availability, etc. triggers catabolic process where damaged or long-lived organelles are wrapped within double-membrane structures called autophagosome that fuse with lysosome to give rise to autolysosome where the low acidic milieu degrades the autophagic cargo to release amino acids, free-fatty acids to circumvent stress. In this backdrop to make the situation worse, another phenomenon called oral-cancer-induced-cachexia leads to a wasting syndrome that affects ninety percent of cases leading to severe decline of muscle mass strength, body fat, extreme weight loss and sharp drop in appetite. Oral cancer induced cachexia is regarded as Objectives: i) Investigate the role of stress management in oral tumor due to crosstalk between autophagy and stress granule to elucidate the critical role of tumor derived secretome that modulate cachexia. ii) Identify the critical metabolites from oral cancers which are fueled by autophagy and have an important role in their growth and proliferation. iii) Development and functional validation of autophagy inhibited oral cancer metabolome to inhibit host cachexia using invitro, invivo and patient derived xenograft models. iv) Investigate the role of autophagy to support the anti-host pathogenic gut microbiome resulting in dysregulation of gut-brain axis signaling of ghrelin/leptin balance in oral cancer Experiments: i) We will inhibit autophagy genetically/pharmacologically in oral cancer cells and coculture with muscle/adipocyte to investigate rescue of cachexia in terms of proliferation, muscle diameter, fat lipid content. Stress granule(SG) production balances stress along with autophagy, so after autophagy inhibition SG mediated secretion effects on cachexia will be checked by western blotting. ii) We will identify the cachexia triggering metabolites being supported by autophagy through metabolomics analysis. Besides this we will also check the key cachexia related secretory factors that autophagy promotes by analysis with multiplex-ELISA, cytokine-arrays. In vitro findings will be validated in vivo and from patient derived xenografts. iii) We will systemically restrict the autophagy fueled metabolites that promote oral cancer recurrence by customized special diet to ensure we are improving cachexia; enhancing therapeutic synergy of autophagy inhibition-based treatments using in vivo and patient derived samples in organoid on chip model. Moreover, we will trace the pattern of grehlin/leptin ratio from in vivo experiment and study alteration in pathogenic gut microbiome by shotgun-sequencing. Significant outcome: We will be able to identify and tell patients what are the metabolites, secretory factors that support oral cancer to induce cachexia. Our study will have a direct translational message to the Indian patients and promise a simple yet effective and powerful take home message about what to eat and what not to particularly for oral cancer cases.