Research Projects

Despite of extensive research effort, cancer occurrence and subsequent cancer deaths are still increasing and continuing as the second leading cause of mortality worldwide. Indeed, it accounts a huge public health concern including India. Cancer is a multifactorial disease driven by genetic, epigenetic, metabolic, and cellular plasticity changes that, influenced by the microenvironment, collectively promote growth, metastasis, recurrence, and therapy resistance.Metabolic disorders like diabetes and obesity worsen various cancers including breast cancer, promoting metastasis, relapse, and therapy resistance. Epidemiological, preclinical, and cell-based studies have linked hyperinsulinemia, altered adiponectin, fatty acids, and estrogens as key drivers for cancer progression. Substantial studies focused mostly on a generic PI3K-AKT-mTOR/ AMPK signalling. Current literature, aligned with Warburg effect, shows that cancer cells acquire metabolic dysregulation especially aerobic glycolysis, lactate fermentation, glutaminolysis and lipid metabolism in early tumorigenesis, even before the acquisition of other crucial cancer hallmarks. In breast cancer with diabesity, key metabolic genes regulating glucose, lipid, and mitochondrial functions are likely dysregulated, driving this shift. In obese breast cancer patients, cancer associated adipocytes fuel tumor growth, cancer cells undergo trans differentiation into adipocyte or osteoblast-like cells, depending on intra cellular metabolites and environmental factors. However, no detailed study of how these transdifferentiated adipocyte-like cells play a role in cancer progression. Our recent studies demonstrated that breast cancer cells trans-differentiate to adipocyte-like cells, where lipid metabolic PLPP4 gene play a vital role in cancer progression and adipogenic activity of cancer cells. Similar to PLPP4, our systematic cancer database analysis found diabetes-associated unexplored gene PHKA1 which is dysregulated in cancer and linked with poor patient survivability. Moreover, RT-PCR analysis found both genes to be elevated in breast malignant tissues, and to be induced in high-glucose condition in breast cancer cells. Based on these findings, we hypothesized that diabetes/obesity induced metabolic stress altered PHKA1 and PLPP4 expression, disrupting glucose and lipid metabolism and mitochondrial function, thereby, promoting transdifferentiating of breast cancer cells into adipocyte-like cells that release exosome to fuel tumor survival and progression. To test the hypothesis, this study aims to investigate how dysregulated PHKA1 and PLPP4 drive glucose and lipid metabolic shifts and how exosomes from adipocyte like breast cancer cells influence tumor progression in diabetes/obesity. Database analysis revealed PHKA1 and PLPP4 as significantly dysregulated in breast cancer. This study will use cell culture, mouse models, and clinical samples to assess how diabetes/obesity influence PHKA1 and PLPP4 in breast cancer progression, employing siRNA/shRNA/CRISPR strategies. Preliminary data show that PHKA1 knockdown reduces oncogenic traits, glycolysis, and mitochondria activity. The proposal investigates whether diabetes alters PLPP4 to disrupt lipid metabolism and drive trans differentiation, highlighting both genes as key players in metabolic disease linked cancer risk. This tumor study in diabetic/obese mice and breast cancer patients will help validate PHKA1 and PLPP4 as potential biomarker for diabesity driven cancer and also reveal that exosome from adipocyte like cancer cells may serve as both progression marker and targeted drug delivery vehicles. Successful completion of this project will bridge the gap between diabesity and breast cancer risk, while opening avenues to: (i) assesses relevance across cancer subtype, (ii) whether this approach capable to find out more metabolic genes (iii) whether targeting these crucial genes can be challenging.