Research Projects

CRC is a leading cause of cancer-related mortality, with increasing incidence rates, particularly in India. One major challenge in CRC treatment is therapy resistance, a complex phenomenon influenced by both genetic and environmental factors. Recent research indicates that mucins, specifically MUC20, and gut microbiota may be key regulators of CRC progression and treatment response. However, the precise role of MUC20 and the gut microbiota in therapy resistance is poorly understood. This project aims to address this gap by exploring the causal relationship between MUC20 and gut microbiota in therapy-resistant CRC. Using a MUC20 transgenic knockout model, we will investigate how MUC20 involved in chemosensitivity. Additionally, through microbiome analysis of CRC patients at various treatment stages, we aim to identify microbial signatures that correlate with drug resistance, offering insights into the microbiota's contribution to treatment outcomes. Scientific objectives: • To elucidate the tumorigenic potential of MUC20 in drug-resistant CRC cell lines • To investigate the cross talk between Muc20 and gut microbiota in treatment response using a transgenic mouse model. Hypothesis/model to be tested: Our central hypothesis is that MUC20 drives therapy resistance in CRC through modulating gut microbiota composition, which, in turn, affects tumor progression and treatment outcomes. We propose that MUC20 knockout mice will exhibit distinct microbiota profiles compared to wild-type (WT) controls, with altered drug response patterns post-treatment. Main experiments: In vitro assays: Generation of drug-resistant CRC cell lines, followed by analysis of MUC20 expression and its impact on tumorigenic potential. CRISPR/Cas9 MUC20 deletion and Xenograft models: Subcutaneous and orthotopic models using knockout of MUC20 in drug-resistant CRC cells to assess tumor growth and therapy response. Establishing a transgenic Muc20-/-CRC mouse model to evaluate sensitivity to chemotherapy. Gut microbiota profiling: Comparative microbiota analysis of MUC20-/- and WT mice post-treatment to identify microbial signatures associated with drug resistance. Clinical validation: Analysis of fecal and tissue samples from CRC patients to validate findings, focusing on microbial markers and MUC20 expression patterns associated with therapy resistance. Significance: This study aims to provide a deeper understanding of MUC20’s role in CRC resistance to therapy, focusing on how gut microbiota modulation influences treatment outcomes. Identifying molecular and microbial signatures linked to MUC20 may lead to novel approaches in CRC precision medicine. If successful, the findings will support the development of new therapeutic strategies targeting MUC20 and identify microbial markers of resistance could pave the way for microbiome-targeted therapies, offering an innovative approach to enhancing CRC treatment efficacy and addressing a critical unmet need in oncology.