Michael T. Hemann

Many human cancers fail to effectively respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. Our lab uses high-throughput screening technology combined with murine stem reconstitution and tumor transplantation systems to investigate the genetic basis for intrinsic and acquired chemotherapeutic resistance.  Our aim is to use these tractable mouse models to identify novel cancer drug targets, as well as strategies for tailoring existing cancer therapies to target the vulnerabilities of specific malignancies.

In vivo fluorescent imaging of a mouse lymphoma following reconstitution with stem cells infected with a GFP-tagged p53 shRNA.In vivo fluorescent imaging of a mouse lymphoma following reconstitution with stem cells infected with a GFP-tagged p53 shRNA.

Understanding microenvironment-mediated chemoresistance

Our laboratory is interested in understanding how specific anatomical sites can be inherently chemoprotective, without presenting a physical barrier to drug delivery. Our recent work has identified mechanisms by which front-line anti-cancer regimens can target most cancer cells yet, paradoxically, promote the survival of a residual tumor burden in specific microenvironments. This process involves the induction of a carefully regulated pro-survival paracrine signaling program emanating from proximal endothelial and infiltrating immune cells. These discoveries have laid a foundation to study basic mechanisms of disease persistence following chemotherapy. For example, our work has shown that the same mechanisms used to protect stem and progenitor cells from physiological stresses can be coopted by tumor cells to evade systemic drug regimens. Thus, we have been able to apply basic tenants of stem cell and developmental biology to direct hypothesis-driven experiments in the realm of cancer therapy – a field that is notoriously reliant upon empirical data.  Importantly, these experiments have also involved the development of new tractable tumor transplantation models in which cancer cells can be rapidly and extensively modified ex vivo and then transplanted into syngeneic, immunocompetent recipient mice. In the process of developing these pre-clinical models, our laboratory has pioneered the application of rapid loss of function screening approaches for use in vivo in mouse models of cancer.  Results from these studies have highlighted significant barriers to therapeutic efficacy, but have also identified new targets that, when inhibited, can potentiate the effects of currently used drug regimens.

Exploring single and combination drug mechanisms of action

Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 years, yet even successful regimens fail to cure many patients. Because these regimens were designed empirically, the precise mechanisms of single component drugs, as well as aggregate mechanisms of combination regimens, are poorly understood. We have combined tractable loss of function genetic tools complementary informatics tools to examine front-line cancer drugs. By using this approach, we have been able to identify unexpected mechanisms of action of very commonly used chemotherapies – information that is critically need to guide the best use of these compounds. Additionally, we have developed approaches to predict combination drug mechanisms of action that are independent of biochemical mechanism and have implications for biomarker discovery as well as for the development of regimens with defined genetic dependencies. Finally, extensions of this technology have provided a basis for studying tumor heterogeneity, tumor evolution and the emergence of resistant clones from heterogeneous tumor populations following therapy.

Corbin Meacham, Lee Lawton, Yadira Soto-Feliciano, Justin Pritchard JR, Brian Joughin, Toby Ehrenberger, Nina Fenouille, Johannes Zuber, Richard Williams, Rick Young, and Michael Hemann. A genome-scale in vivo loss-of-function screen identifies Phf6 as a lineage-specific regulator of leukemia cell growth. Genes Dev. 2015;29(5):483-488.

Boyang Zhao, Justin Pritchard, Doug Lauffenburger, and Michael Hemann. Addressing genetic tumor heterogeneity through computationally predictive combination therapy. Cancer Discov. 2014;4(2):166-174.

Christian Pallasch, Ilya Leskov, Christian Braun, Danielle Vorholt , Adam Drake, Yadira Soto-Feliciano, Eric Bent , J Schwamb, B Iliopoulo, N Kutsch, Nico van Rooijen, Lukas Frenzel, Clemens Wendtner, L Heukamp, KA Kreuzer, Michael Hallek, Jianzhu Chen and Michael Hemann. Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell. 2014;156(3):590-602.

Justin Pritchard , Peter Bruno, Luke Gilbert, Kelsey Capron, Doug Lauffenburger, and Michael Hemann. Defining principles of combination drug mechanisms of action. Proc Natl Acad Sci USA. 2013;110(2):E170-9.

Hai Jiang, Justin Pritchard, Richard Williams, Doug Lauffenburger and Michael Hemann. A mammalian functional-genetic approach to characterizing cancer therapeutics. Nat. Chem. Biol. 2011; 7(2):92-100.

Luke Gilbert and Michael Hemann. DNA damage-mediated induction of a chemoresistant niche. Cell. 2010; 143(3):355-366.