Associate Professor of Biology
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"Many human cancers do not respond to treatment, and often times those that initially respond eventually acquire drug resistance. Our lab uses high-throughput screening technology in combination with tractable pre-clinical mouse models to investigate basic mechanisms of intrinsic and acquired drug resistance. Our goal is to identify novel cancer drug targets, as well as strategies for tailoring drug regimens to target protective mechanisms used by cancers to evade and escape cancer therapy."
Michael Hemann is an associate professor in the MIT Department of Biology, a member of the Koch Institute, and an associate member of the Broad Institute. He earned his bachelor’s degree in molecular biology and biochemistry from Wesleyan University in 1993, and a doctorate in human genetics from the Johns Hopkins University School of Medicine in 2001. For his doctoral work, he was awarded the Harold M. Weintraub Graduate Student Award from the Fred Hutchinson Cancer Research Center. He was a post-doctoral fellow in the laboratory of Scott Lowe at Cold Spring Harbor Laboratory in New York, where he was supported by a Helen Hay Whitney Fellowship and a Lauri Strauss Leukemia Foundation Grant. In 2006, Professor Hemann joined the MIT faculty as an assistant professor. He has since been awarded a V Foundation Fellowship and was selected as a Rita Allen Scholar.
Many tumors fail to effectively respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. While drug resistance has been observed since the earliest chemotherapeutic application, relatively little is known about the genetics of drug response. Thus, chemotherapy is commonly given without regard for the specific genetic changes present in a given tumor. This current clinical approach is problematic for a number of reasons. First, patients are frequently given chemotherapies that have little or no chance of success. Second, tumor vulnerabilities resulting from specific genetic changes are rarely considered prior to chemotherapy, so the “right therapy” is generally not matched with the “right tumor”. Third, combination therapies are currently assembled by random trial and error, rather than through a genuine understanding of why certain drugs may work together. Finally, potentially effective drugs frequently fail in clinical trials due to an inability to identify small patient populations in which these drugs would work. The goal of this work is to use powerful new technologies to identify genetic changes that influence the action of chemotherapy. By understanding why cancer therapies fail, we hope to develop new treatments and treatment strategies that lead to durable responses and, ultimately, cures.
Using a diverse set of murine tumor models, we have been able to show that paracrine factors in the tumor microenvironment modulate tumor cell survival following the administration of the genotoxic chemotherapeutics. Specifically, prosurvival cytokines are released from select tumor-bearing sites in response to DNA damage, creating “chemo-resistant niches” that promote the persistance of a minimal residual tumor burden and serve as a reservoir for eventual tumor relapse. Disruption of this chemo-protective cytokine signaling or ablation of the protective microenvironment potentiates the action of doxorubicin. Notably, cytokines are released acutely from normal cells following genotoxic stress. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in distinct anatomical locations from drug action.
We are also interested in understanding understand how the microenvironment affects the response to immunotherapy, including CAR-T cells. CAR-T cells (modified T cells) represent one of the most exciting new therapies in cancer and have been shown to be effective in the treatment of B cell cancers, yet these therapies also frequently fail. We have developed a strategy for generating mouse CAR-T cells and screening B leukemia cells in vivo for genetic alterations that can promote CAR-T cell resistance. This project is only possible in mouse models, as we require an intact functional in vivo immune system to perform these studies. We have also expanded the use of this approach to treatment studies involving pancreas cancer and glioblastoma.
The Hemann lab makes use of syngeneic tumor transplantation experiments model tumor development and therapeutic response. Initially, this work focused on gene overexpression studies involving deregulated oncogenes. Subsequently, we have expanded the utility of this adoptive transfer system using stable RNAi and CRISPR. Using retroviral infection tumor cells, we have successfully generated tumors which biochemically and phenotypically suppressed gene expression over extended periods in vivo. This technology has allowed us to accelerate and expand our analysis of the impact of defined lesions both on tumor onset and therapeutic response.
We have adapted screening approaches traditionally reserved for single-cell organisms or simple metazoans for use in mammals. Specifically, we used loss of function pool-based screening to carry out high-throughput forward genetics in mice in vivo. In some contexts, as many as 25,000 cells contribute to a given malignancy following tail vein injection, and, consequently, nearly 25,000 loss of function phenotypes can be screened in the context of an individual mouse. Notably, the shRNAs or gRNAs that enrich and deplete in vivo differ strikingly from those that enrich and deplete in culture, implicating the tumor microenvironment as a central contributor to tumors homeostasis. These data suggest that large-scale in vivo screens are readily feasible with a limited cohort of mice – an approach that we extensively use in ongoing experiments. Importantly, this strategy can be used to screen both hematopoietic and solid tumors and has led to the identification of critical drug targets and processes in glioblastoma and pancreatic cancers.
We have generated several shRNA vectors that mediate resistance to conventional chemotherapeutics in vivo. We are currently expanding this approach, through the use of targeted RNAi libraries, to assess the role of thousands of cancer-relevant genes in the response of diverse tumor types to a wide array of chemotherapeutics. This strategy allows us to perform genetic screens for mediators of chemotherapeutic response in a relevant therapeutic setting.
Importantly, this approach has broad flexibility. First, distinct tumor types can be examined to determine the effect of tumor genotype on mechanisms of chemotherapeutic resistance. Second, the pattern of shRNAs conferring drug resistance in an individual tumor treated with established chemotherapeutic can serve as a "treatment fingerprint", such that the mechanisms of action of novel chemotherapeutics may be deduced by comparison with these established patterns. Third, in addition to examining drug resistance, we can use representational approaches to identify shRNAs that promote sensitivity to specific drugs. In doing so, we hope to identify drug targets whose inactivation synergizes with existing anti-cancer therapies.
Learn more about the Hemann lab’s work in system biology and how they use high throughput genetics in model systems to screen for mechanisms of drug resistance by watching the video: "Inside the Lab: Michael H. Hemann, Ph.D."
Dalin S, Sullivan MR, Lau AN, Grauman-Boss B, Mueller HS, Kreidl E, Fenoglio S, Luengo A, Lees JA, Vander Heiden MG, Lauffenburger DA, Hemann MT. 2019. Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance. Cancer Res 79: 5723–5733.
Soto-Feliciano YM, Bartlebaugh JME, Liu Y, Sánchez-Rivera FJ, Bhutkar A, Weintraub AS, Buenrostro JD, Cheng CS, Regev A, Jacks TE, et al. 2017. PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes. Genes Dev 31: 973–989.
Bruno PM, Liu Y, Park GY, Murai J, Koch CE, Eisen TJ, Pritchard JR, Pommier Y, Lippard SJ, Hemann MT. 2017. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat Med 23: 461–471.
Zhao B, Sedlak JC, Srinivas R, Creixell P, Pritchard JR, Tidor B, Lauffenburger DA, Hemann MT. 2016. Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution. Cell 165: 234–246.
Bent EH, Gilbert LA, Hemann MT. 2016. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev 30: 1811–1821.
Zhao B, Pritchard JR, Lauffenburger DA, Hemann MT. 2014. Addressing genetic tumor heterogeneity through computationally predictive combination therapy. Cancer Discov 4: 166–174.
Pallasch CP, Leskov I, Braun CJ, Vorholt D, Drake A, Soto-Feliciano YM, Bent EH, Schwamb J, Iliopoulou B, Kutsch N, et al. 2014. Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell 156: 590–602.
Pritchard JR, Bruno PM, Gilbert LA, Capron KL, Lauffenburger DA, Hemann MT. 2013. Defining principles of combination drug mechanisms of action. Proc Natl Acad Sci USA 110: E170-179.
Gilbert LA, Hemann MT. 2012. Context-specific roles for paracrine IL-6 in lymphomagenesis. Genes Dev 26: 1758–1768.
Gilbert LA, Hemann MT. 2010. DNA damage-mediated induction of a chemoresistant niche. Cell 143: 355–366.
Jiang H, Reinhardt HC, Bartkova J, Tommiska J, Blomqvist C, Nevanlinna H, Bartek J, Yaffe MB, Hemann MT. 2009. The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev 23: 1895–1909.