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Mandar Deepak Muzumdar, MD

Associate Professor of Genetics and of Internal Medicine (Medical Oncology).; Member, Yale Cancer Biology Institute; Scientific Director, Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center; Co-Director of Pancreas Program, Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center; Associate Professor of Internal Medicine, Medical Oncology

Contact Information

Mandar Deepak Muzumdar, MD

Lab Location

Office Location

Mailing Address

  • Genetics

    Department of Genetics, P.O. Box 208005

    New Haven, CT 06520-8005

    United States

Muzumdar Lab

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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

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Tracing clonal evolution of pancreatic cancer in mice

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