Charles W. (1955) and Jennifer C. Johnson Clinical Investigator
"Our laboratory combines approaches from cell biology, systems biology, and bioinformatics to understand tumor heterogeneity and how it underlies treatment failure. In particular, we are interested in the molecular mechanisms that govern the behavior of genes in networks and give rise to cell behaviors like malignancy. Understanding how the behavior of single cells is dictated by the structure of gene regulatory programs will give us new insights into how tumors evolve and persist."
Salil Garg, MD, PhD, is the Charles W. and Jennifer C. Johnson Clinical Investigator at the Koch Institute for Integrative Cancer Research at MIT. Trained through the Harvard/MIT-MD PhD Program at Harvard Medical School, Dr. Garg completed his doctoral thesis in the laboratory of Michael Brenner studying cellular trafficking in the immune system. Following clinical training, Dr. Garg completed postdoctoral work in the laboratory of KI member, MIT Institute Professor, and Nobel Laureate Phillip A. Sharp. He is board certified in clinical pathology and completed a fellowship in molecular genetic pathology at Massachusetts General Hospital, where he currently practices. In 2017, Dr. Garg was named a STAT Wunderkind, an accolade that honors the brightest young minds in life science for their work in academia, industry, and in the clinic.
The Garg Lab aims to define the molecular drivers in mutationally bland cancers to develop new diagnostics and therapies. Next-generation sequencing has led to an explosion in understanding the DNA changes that lead to malignancy and led to new diagnostic tests in the clinic. Yet, not all malignancies have been impacted equally. Many pediatric malignancies such as ependymoma and subclasses of leukemia show no or few recurrent DNA changes, complicating attempts at personalized therapy. Interestingly, these mutationally bland cancers and many others show extensive tumor heterogeneity arising spontaneously from single cells.
Understanding this intrinsic heterogeneity arising at a single cell level is key to unlocking the pathogenesis of cancers that may have epigenetic drivers. These malignancies often involve de-differentiation with inappropriate expression of embryonic developmental programs. An embryonic cell model system has been developed that shows intrinsic heterogeneity in generating different functional cell states. The states transition in part through coordinated expression changes of many genes in functional networks that depend on microRNAs, post-transcriptional regulatory small RNAs that bind gene products.
The Garg Lab is interested in how microRNAs stabilize gene networks in embryonic cells and in the malignant cell state. Their hypothesis is that transitions in microRNA expression generate changes in cell behavior and can drive the malignant cell state in mutationally bland cancers. The lab is testing these ideas using techniques from cell biology, systems biology, and genomics. Additionally, the Garg Lab is working closely with the Anderson and Sharp Labs to develop single cell microRNA sequencing. This platform technology will allow researchers to test whether changes in microRNA expression precede changes in cell behavior and will provide a new diagnostic for early cancer detection.
Garg S, Sharp PA. 2016. Single cell variability guided by microRNAs. Science 352: 1390–1391.
Garg S, Brenner MB. 2015. RNAi screens of lysosomal trafficking. Methods Cell Biol 126: 119–138.
Michelet X, Garg S, Wolf BJ, Tuli A, Ricciardi-Castagnoli P, Brenner MB. 2015. MHC Class II Presentation Is Controlled by the Lysosomal Small GTPase, Arl8b. J Immunol 194: 2079–2088.
Tuli A, Thiery J, James AM, Michelet X, Sharma M, Garg S, Sanborn KB, Orange JS, Lieberman J, Brenner MB. 2013. Arf-like GTPase Arl8b regulates lytic granule polarization and natural killer cell-mediated cytotoxicity. Mol Biol Cell 24: 3721–2735.
Barral DC, Garg S, Casalou C, Watts GF, Sandoval JL, Ramalho JS, Hsu VW, Brenner MB. 2012. Arl13b Regulates Endocytic Recycling Traffic. PNAS 109: 21354–21359.
Garg S, Sharma M, Ung C, Barral DC, Hava DL, Veerapen N, Besra GS, Hacohen N, Brenner MB. 2011. Lysosomal Trafficking, Antigen Presentation, and Microbial Killing Are Controlled by the Arf-like GTPase Arl8b. Immunity 35: 182–193.
Cohen NR, Garg S, Brenner MB. 2009. Antigen Presentation by CD1 Lipids, T Cells, and NKT Cells in Microbial Immunity. Adv Immunol 102: 1–94.
van den Elzen P, Garg S, León L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB. 2005. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437: 906–910.