Biology subjects

Varshney, R. R.

Publications and source records attributed to Varshney, R. R..

3 recordsLinked to original sources

bioRxiv2025

Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas

High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

cancer biology↗

bioRxiv2025

Hypertrophic adipocytes increase extracellular vesicle-mediated lipid release and reprogram breast cancer cell metabolism

Primary adipocytes possess a dramatic capacity to expand and retract in volume, leading to high variability in cell size within and between individuals. Yet, how adipocyte size impacts cell function remains unclear as adipocyte size is not tunable with traditional experimental approaches, forcing previous work to rely on correlative studies. Here, we develop protocols to separate primary adipocytes from the same donor into large and small populations and maintain these size-sorted cells in culture. Using these methods, we perform transcriptomic, lipidomic, and functional analyses on large and small adipocytes across two orthogonal mouse models of obesity and validate our results with human clinical samples. Our findings indicate that changes to cell size, rather than global differences mediated by weight gain, drive the transcriptional response of primary adipocytes to obesity. Moreover, large adipocytes shift from a traditional, lipase-mediated mode of lipid release to a non-canonical, extracellular vesicle-mediated mechanism. In functional coculture studies, this change promotes lipid accumulation in neighboring breast cancer cells, increasing their migration and proliferation via enhanced tumor cell fatty acid oxidation. Consistent with our experimental data, human patients with large adipocytes present with greater rates of dyslipidemia and higher concentrations of fasting triglycerides, even when accounting for differences in body mass index. Collectively, our results provide direct evidence that large and small adipocytes from the same donor differ in gene expression, lipid composition, and function with implications for the management of adipose tissue-related pathologies such as breast cancer.

cell biology↗

bioRxiv2024

Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells

BackgroundLipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER+ breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor. MethodsER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth. 13C2-acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640. ResultsEndocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets. 13C2-acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth. Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640. ConclusionEndocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.

cancer biology↗