Mandar Deepak Muzumdar, MD
Research & Publications
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Research Summary
Despite innovations in combination chemotherapy, targeted therapies, and immunotherapies, most advanced cancers remain incurable. Deciphering the mechanisms that govern the initiation, progression, and maintenance of cancer will facilitate the development of novel strategies for prevention and therapy. For cancers to arise, cells must acquire the capacity for sustained proliferation while overcoming both intrinsic evolutionary constraints and constraints imposed by the host environment. These properties may be attained through the sequential acquisition of genetic mutations in proto-oncogenes and tumor suppressor genes. Comprehensive genome sequencing efforts have catalogued human cancer mutations, enabling the use of therapies that target these mutated oncoproteins. Nonetheless, cancers frequently evade target inhibition. We recently demonstrated, for example, that pancreatic cancer cells tolerate genetic ablation of their initiating oncogene KRAS through rewiring of signal transduction. Similar adaptive mechanisms (signaling-based, transcriptional, epigenetic, and metabolic) play a critical role in the maintenance of advanced cancers in the absence of new mutations. In contrast, how non-mutational adaptations impact the earlier stages of tumorigenesis remains poorly understood.
Using genetically-engineered mouse models that closely recapitulate human lung and pancreatic cancers, we have shown that gene mutations are permissive, but insufficient, to drive clonal cancer evolution, consistent with the need for additional cellular adaptations. Furthermore, we have demonstrated that host adaptations to environmental stresses, such as obesity, may facilitate tumor progression in the absence of new mutations. Our research focuses on elucidating the molecular basis of these tumor cell and host adaptations in hopes of defining new approaches for the prevention and treatment of these recalcitrant cancers.
Coauthors
Research Interests
Adaptation, Biological; Carcinoma, Non-Small-Cell Lung; Diabetes Mellitus; Gene Expression Regulation; Neoplasms; Neoplastic Processes; Obesity; Oncogenes; Precancerous Conditions; Genes, Tumor Suppressor; Tumor Escape; MAP Kinase Signaling System; Carcinoma, Pancreatic Ductal; Animals, Genetically Modified; Cell Proliferation; Metabolome; Transcriptome; Clonal Evolution; Carcinogenesis
Research Image
Tracing clonal evolution of pancreatic cancer in mice
Selected Publications
- Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal AdenocarcinomaChung KM, Singh J, Lawres L, Dorans KJ, Garcia C, Burkhardt DB, Robbins R, Bhutkar A, Cardone R, Zhao X, Babic A, Vayrynen SA, Dias Costa A, Nowak JA, Chang DT, Dunne RF, Hezel AF, Koong AC, Wilhelm JJ, Bellin MD, Nylander V, Gloyn AL, McCarthy MI, Kibbey RG, Krishnaswamy S, Wolpin BM, Jacks T, Fuchs CS, Muzumdar MD. Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma Cell 2020, 181: 832-847.e18. PMID: 32304665, PMCID: PMC7266008, DOI: 10.1016/j.cell.2020.03.062.
- Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings.Mastracci T, Apte M, Amundadottir L, Alvarsson A, Artandi S, Bellin M, Bernal-Mizrachi E, Caicedo A, Campbell-Thompson M, Cruz-Monserrate Z, El Ouaamari A, Gaulton K, Geisz A, Goodarzi M, Hara M, Hull-Meichle R, Kleger A, Klein A, Kopp J, Kulkarni R, Muzumdar M, Naren A, Oakes S, Olesen S, Phelps E, Powers A, Stabler C, Tirkes T, Whitcomb D, Yadav D, Yong J, Zaghloul N, Pandol S, Sander M. Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings. Diabetes 2023, 72: 433-448. PMID: 36940317, PMCID: PMC10033248, DOI: 10.2337/db22-0942.
- Oligomeric distribution of membrane proteins in native-membrane environment at nanoscale spatial and single-molecule resolutionWalker G, Brown C, Ge X, Gupta K, Muzumdar M, Bhattacharyya M. Oligomeric distribution of membrane proteins in native-membrane environment at nanoscale spatial and single-molecule resolution Biophysical Journal 2023, 122: 457a. DOI: 10.1016/j.bpj.2022.11.2457.
- Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic DiseasesMastracci T, Apte M, Amundadottir L, Alvarsson A, Artandi S, Bellin M, Bernal-Mizrachi E, Caicedo A, Campbell-Thompson M, Cruz-Monserrate Z, Ouaamari A, Gaulton K, Geisz A, Goodarzi M, Hara M, Hull-Meichle R, Kleger A, Klein A, Kopp J, Kulkarni R, Muzumdar M, Naren A, Oakes S, Olesen S, Phelps E, Powers A, Stabler C, Tirkes T, Whitcomb D, Yadav D, Yong J, Zaghloul N, Sander M, Pandol S. Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases Pancreas 2022, 51: 1061-1073. PMID: 37078927, DOI: 10.1097/mpa.0000000000002170.
- 5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STINGTian J, Zhang D, Kurbatov V, Wang Q, Wang Y, Fang D, Wu L, Bosenberg M, Muzumdar MD, Khan S, Lu Q, Yan Q, Lu J. 5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STING The EMBO Journal 2021, 40: e106065. PMID: 33615517, PMCID: PMC8013832, DOI: 10.15252/embj.2020106065.
- Identification of DHODH as a therapeutic target in small cell lung cancerLi L, Ng SR, Colón CI, Drapkin BJ, Hsu PP, Li Z, Nabel CS, Lewis CA, Romero R, Mercer KL, Bhutkar A, Phat S, Myers DT, Muzumdar MD, Westcott PMK, Beytagh MC, Farago AF, Vander Heiden MG, Dyson NJ, Jacks T. Identification of DHODH as a therapeutic target in small cell lung cancer Science Translational Medicine 2019, 11 PMID: 31694929, PMCID: PMC7401885, DOI: 10.1126/scitranslmed.aaw7852.
- iRGD-guided tumor-penetrating nanocomplexes for therapeutic siRNA delivery to pancreatic cancerLo JH, Hao L, Muzumdar MD, Raghavan S, Kwon EJ, Pulver EM, Hsu F, Aguirre AJ, Wolpin BM, Fuchs CS, Hahn WC, Jacks T, Bhatia SN. iRGD-guided tumor-penetrating nanocomplexes for therapeutic siRNA delivery to pancreatic cancer Molecular Cancer Therapeutics 2018, 17: molcanther.1090.2017. PMID: 30097486, PMCID: PMC6298224, DOI: 10.1158/1535-7163.mct-17-1090.
- Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic CancerTao Z, Muzumdar MD, Detappe A, Huang X, Xu ES, Yu Y, Mouhieddine TH, Song H, Jacks T, Ghoroghchian PP. Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer Nano Letters 2018, 18: 2195-2208. PMID: 29533667, PMCID: PMC5957485, DOI: 10.1021/acs.nanolett.7b04043.
- Adaptive and reversible resistance to Kras inhibition in pancreatic cancer cellsChen PY, Muzumdar M, Dorans KJ, Robbins R, Bhutkar A, Del Rosario A, Mertins P, Qiao J, Schafer AC, Gertler F, Carr S, Jacks T. Adaptive and reversible resistance to Kras inhibition in pancreatic cancer cells Cancer Research 2018, 78: canres.2129.2017. PMID: 29279356, PMCID: PMC5837062, DOI: 10.1158/0008-5472.can-17-2129.
- Survival of pancreatic cancer cells lacking KRAS functionMuzumdar MD, Chen PY, Dorans KJ, Chung KM, Bhutkar A, Hong E, Noll EM, Sprick MR, Trumpp A, Jacks T. Survival of pancreatic cancer cells lacking KRAS function Nature Communications 2017, 8: 1090. PMID: 29061961, PMCID: PMC5653666, DOI: 10.1038/s41467-017-00942-5.
- Early tumor detection afforded by in vivo imaging of near-infrared II fluorescenceTao Z, Dang X, Huang X, Muzumdar MD, Xu ES, Bardhan NM, Song H, Qi R, Yu Y, Li T, Wei W, Wyckoff J, Birrer MJ, Belcher AM, Ghoroghchian PP. Early tumor detection afforded by in vivo imaging of near-infrared II fluorescence Biomaterials 2017, 134: 202-215. PMID: 28482280, DOI: 10.1016/j.biomaterials.2017.04.046.
- Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancersMuzumdar MD, Dorans KJ, Chung KM, Robbins R, Tammela T, Gocheva V, Li CM, Jacks T. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers Nature Communications 2016, 7: 12685. PMID: 27585860, PMCID: PMC5025814, DOI: 10.1038/ncomms12685.
- Targeting the HGF/c-MET Pathway in Hepatocellular CarcinomaGoyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma Clinical Cancer Research 2013, 19: 2310-2318. PMID: 23388504, PMCID: PMC4583193, DOI: 10.1158/1078-0432.ccr-12-2791.
- A global double‐fluorescent Cre reporter mouseMuzumdar MD, Tasic B, Miyamichi K, Li L, Luo L. A global double‐fluorescent Cre reporter mouse Genesis 2007, 45: 593-605. PMID: 17868096, DOI: 10.1002/dvg.20335.
- Modeling sporadic loss of heterozygosity in mice by using mosaic analysis with double markers (MADM)Muzumdar MD, Luo L, Zong H. Modeling sporadic loss of heterozygosity in mice by using mosaic analysis with double markers (MADM) Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 4495-4500. PMID: 17360552, PMCID: PMC1810340, DOI: 10.1073/pnas.0606491104.
- Mosaic Analysis with Double Markers in MiceZong H, Espinosa JS, Su HH, Muzumdar MD, Luo L. Mosaic Analysis with Double Markers in Mice Cell 2005, 121: 479-492. PMID: 15882628, DOI: 10.1016/j.cell.2005.02.012.
- Sonic Hedgehog Is Required for Progenitor Cell Maintenance in Telencephalic Stem Cell NichesMachold R, Hayashi S, Rutlin M, Muzumdar M, Nery S, Corbin J, Gritli-Linde A, Dellovade T, Porter J, Rubin L, Dudek H, McMahon A, Fishell G. Sonic Hedgehog Is Required for Progenitor Cell Maintenance in Telencephalic Stem Cell Niches Neuron 2003, 40: 189-190. DOI: 10.1016/s0896-6273(03)00593-2.