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Bishal Paudel

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I am a Postdoc in the Department of Biomedical Engineering at the University of Virginia. My research interest is in cancer systems biology, particularly understanding the origins of cellular heterogeneity, and how it gives rise to different cellular states, cell differentiation, drug resistance, and other emergent population behaviors.

Current Interests and Projects:

Tumor Heterogeneity & Cellular Identity, Metabolic Reprogramming

Cancer cells are highly heterogeneous, and this heterogeneity is manifested in many forms: cellular phenotype, genome, epigenome, fitness, metabolic states etc. Intriguingly, what makes cancer cells unique is their ability to alter their phenotype when exposed to fluctuating environments. Cancer cells achieve this plasticity by rewiring the underlying gene regulatory networks that gives them a unique identity in the first place, alter their metabolic needs depending on the environment, and most importantly establish cell-cell communication through which they achive an optimum population behavior. Understanding how cancer cells are unique, their inherent ability to alter their phenotype, and how emergent behaviors arise will be critical in not only deciphering the early steps of tumorigenesis, but also in designing rational strategies to target them.

Publications

  • Paudel BB, Lewis JE, Hardeman KN, Hayford CE, Robbins CJ, Stauffer PE, Cordeanu GS, Sherrod SD, McLean JA, Kemp, ML, & Quaranta, V. “An Integrative Gene Expression and Mathematical Flux-Balance Analysis Identifies Targetable Redox Vulnerabilities in Melanoma Cells.” Cancer Res. 2020;80:4565–77. PaperLink
  • Jia D*, Paudel BB*, Hayford CE, Hardeman KN, Onuchic JN, Levine H, Quaranta V. “Drug-tolerant idling melanoma cells exhibit theory-predicted metabolic low-low phenotype.” Front. Oncol. 2020; 10: 1426. PaperLink *(Equal contributions)
  • Paudel BB & Quaranta, V. “Metabolic Plasticity Meets Gene Regulation.” Proceedings of the National Academy of Sciences of the United States of America. 2019; 116(9):3370-3372. PaperLink

Nongenetic Mechanisms of Drug Resistance and Tolerance

We now appreciate that seemingly homogenous cancer cells respond differently to therapies, and anti-cancer therapies only kill a fraction of tumor cells. Such phenotypes may arise from cell subpopulations having unique cell identities and often these phenotypes evolve over time both in drug-naïve and drug-perturbed conditions. Drug resistance is often thought to arise from pre-existing genetic mutations, but accumulating evidence now points to several nongenetic mechanisms that give rise to drug-tolerance and ultimately tumor relapse.

Publications

  • Paudel BB, Harris LA, Hardeman KN, Abugable AA, Hayford CE, Tyson DR, Quaranta, V. A Nonquiescent “Idling” Population State in Drug-Treated, BRAF-Mutated Melanoma. Biophysical Journal. 2018; 114(6):1499-1511. PaperLink Journal Cover: March 27, 2018 (Volume 114, Issue 6) Featured on: The Official Blog of Biophysical Society
  • Hardeman KN, Peng C, Paudel BB, Meyer CT, Luong T, Tyson DR, Young JD, Quaranta V, Fessel JP. “Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.” Scientific Reports. 2017;7. PaperLink

Systems Pharmacology and Rational Drug combination

Understanding how cancer cells respond to anti-cancer therapies will be critical in designing appropriate interventions in successful cancer therapy. Systems pharmacology requires a robust approach in quantifying drug responses, in delienating pre-existing clonal heterogeneity, in understanding varied mode of drug actions, and their interactions.

Publications

  • Paudel BB & Quaranta, V. “Dynamics of drug response informs rational combination regimens.” Sci. Signal. 2019; 12, eaax9742. PaperLink
  • Meyer CT*, Wooten DJ*, Paudel BB*, Bauer J, Hardeman KN, Westover D, Lovly CM, Harris LA, Tyson DR & Quaranta V. “Quantifying the synergy of drug combinations with respect to potency and efficacy.” Cell Systems. 2019. 8(2):97-108. PaperLink *(Equal contributions)
  • Harris LA, Frick PL, Garbett SP, Hardeman KN, Paudel BB, Lopez CF, Quaranta V, Tyson DR. “An unbiased metric of anti-proliferative drug effect in vitro.” Nat Methods. 2016;13(6):497–500. PaperLink
  • Frick PL, Paudel BB, Tyson DR, Quaranta V. “Quantifying heterogeneity and dynamics of clonal fitness in response to perturbation.” Journal of cellular physiology. 2015 Jul 1;230(7):1403-12. PaperLink