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Biology subjects

Priyadarshi, S.

Publications and source records attributed to Priyadarshi, S..

3 recordsLinked to original sources

Next-Gen Profiling of Tumor-resident Stem Cells using Machine learning

Tumor-resident stem cells, also known as cancer stem cells (CSCs), constitute a subgroup within tumors, play a crucial role in fostering resistance to treatment and the recurrence of tumors, and pose significant challenges for conventional therapeutic methods. Existing approaches for identifying CSCs face notable hurdles related to scalability, reproducibility, and technical consistency across different cancer types due to the adaptable nature of CSCs. In this context, we introduce OSCORP, an innovative machine-learning-driven approach. This methodology quantifies and identifies CSCs, achieving almost 99% accuracy using biopsy bulk RNAseq data. OSCORP leverages genetic similarities between normal and cancer stem cells. By categorizing CSCs into four distinct yet dynamic potency states, this approach provides insights into the differentiation landscape of CSCs, unveiling previously undisclosed facets of tumor heterogeneity. In evaluations conducted on patient samples across 22 cancer types, OSCORP revealed clinical, transcriptomic, and immunological signatures associated with each CSC state. It has emerged as a comprehensive tool for understanding and addressing the complexities of cancer stem cells. Ultimately, OSCORP opens up new possibilities for more effective personalized cancer therapies and holds the potential to serve as a clinical tool for monitoring patient-specific CSC changes during treatment or follow-up care.

cancer biology↗

Methotrexate-modulated talin-dynamics drives cellular mechanical phenotypes via YAP signalling

Methotrexate is a well-known antineoplastic drug used to prevent cancer aggravation. Despite being a targeted therapeutic approach, its administration comes with the risk of cancer recurrence, plausibly through its proven off-target effect on focal adhesions. Since FA dynamics is dependent on force transmission through its constituent proteins, including talin, methotrexate might affect the mechanical activity of these proteins. Here we have combined single-molecule studies, computational dynamics, cell-based assays, and genomic analysis to unveil the focal adhesion-regulating role of methotrexate central to its effect on talin dynamics and downstream pathways. Interestingly, our single-molecule force spectroscopic study shows that methotrexate modulates the bimodal force distribution of talin in a concentration-dependent manner. Steered molecular dynamics reveal that methotrexate-talin interactions alter talin mechanical stability exposing their vinculin binding sites. Finally, we found that methotrexate-regulated talin-dynamics remodel cancer cell mechanical phenotypes like cell polarity, adhesion, and migration by regulating talin-vinculin association-mediated YAP signaling. These results further correlate with genomic analysis of methotrexate-treated patients, demonstrating its clinical importance. Taken together, these findings disseminate the effects of methotrexate-modulated mechanosensitivity of adhesion proteins on cellular events.

cell biology↗

An Igh novel enhancer modulates antigen receptor diversity by determining locus conformation

The Igh locus is organized into a developmentally regulated topologically associated domain (TAD) that is divided into subTADs. Here we identify a series of novel enhancers (NEs) that collaborate to configure the locus, determine transcriptional potential in over a hundred functional VH genes and their usage in V(D)J recombination. NE1 engages in a network of long-range interactions that interconnect the subTADs and the recombination center at the DHJH gene cluster. Deletion of NE1 alters discrete chromatin loops, higher order locus conformation, locus-wide VH gene transcription and regional V gene utilization that is linked to a greatly reduced splenic B1 B cell compartment. NE1 blocks long-range loop extrusion that in turn contributes to locus contraction and determines the proximity of distant VH genes to the recombination center. NE1 is a critical architectural element that coordinates chromatin conformational states that favor VH gene transcription or V(D)J rearrangement.

immunology↗