OUR FOCUS
Macrophage dysfunction is a hallmark of chronic sterile inflammatory diseases including cancer, atherosclerosis, and obesity/type 2 diabetes. Because macrophages are highly influenced by their environment, it is essential to understand how disease-specific changes to tissues trigger specific pathways in macrophages to drive pathogenesis. Moreover, the relationship between disease-producing macrophage pathways to those required for pathogen clearance is largely unknown, which is important because attempts to therapeutically target macrophages must preserve their host defense function. Comparing and contrasting macrophages across a spectrum of diseases is therefore required to elucidate disease-specific mechanisms, and to develop therapeutics that are both efficacious and safe.
Our long-term goal is to develop a robust research program that uses a multi-disease approach to develop a comprehensive understanding of macrophage biology, and translate this mechanistic understanding to develop therapeutics across a spectrum of human disease. To this end, we are developing a new biologic for the treatment of many cancers, a small molecule that restores anti-cancer immunity, and small molecules that attenuate the deleterious inflammation during metabolic diseases while preserving the inflammation required for host defense.
our approach
Our research combines proteomics, bioinformatics, immunologic, biochemistry, and functional approaches to study the role of macrophages across a spectrum of diseases. We implement a discovery-based approach to identify altered protein abundance patterns in disease states, and use data-driven hypotheses to interrogate the mechanisms by which macrophages influence disease progression. All projects involve a dynamic interplay between molecular, cellular, mouse, and human studies. This approach allows us to leverage the power of in vitro studies and mouse genetics to test novel mechanistic hypotheses while maximizing the potential for obtaining information that is clinically impactful.
Macrophage accumulation in tissues promotes disease. Left: Tumor-associated macrophages in early TNBC tumors. Middle: Macrophages forming crown-like structures in obese adipose tissue. Right: Macrophages engulf cholesterol to form foam cells in artery wall plaques.
Selected publications
A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours
Chang Cui, Kasturi Chakraborty, Xu Anna Tang, Kelly Q. Schoenfelt, Alexandria Hoffman, Ariane Blank, Blake McBeth, Natalie Pulliam, Catherine A. Reardon, Swati A. Kulkarni, Tomas Vaisar, Andrea Ballabio, Yamuna Krishnan*, and Lev Becker*
NATURE NANOTECHNOLOGY (2021).
Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis
Chang Cui, Kasturi Chakraborty, Xu Anna Tang, Guolin Zhou, Kelly Q. Schoenfelt, Kristen M. Becker, Alexandria Hoffman, Ya-Fang Chang, Ariane Blank, Catherine A. Reardon, Hilary A. Kenny, Tomas Vaisar, Ernst Lengyel, Geoffrey Greene, and Lev Becker*
Cell 184.12 (2021): 3163-3177.
metabolic regulation of gene expression by histone lactylation
Di Zhang, Zhanyun Tang, He Huang, Guolin Zhou, Chang Cui, Yejing Weng, Wenchao Liu, Sunjoo Kim, Sangkyu Lee, Mathew Perez-Neut, Jun Ding, Daniel Czyz, Rong Hu, Zhen Ye, Maomao He, Y. George Zheng, Howard A. Shuman, Lunzhi Dai, Bing Ren, Robert G. Roeder, Lev Becker* and Yingming Zhao*
Nature 574.7779 (2019): 575-580.
Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer
Payal Tiwari, Ariane Blank, Chang Cui, Kelly Q. Schoenfelt, Guolin Zhou, Yanfei Xu, Galina Khramtsova, Funmi Olopade, Ajay M. Shah, Seema A. Khan, Marsha Rich Rosner*, and Lev Becker*
Journal of Experimental Medicine 216.6 (2019): 1345-1358.
A DNA-based fluorescent reporter maps HOCl production in the maturing phagosome
Shareefa Thekkan, Maulik S. Jani, Chang Cui, Krishna Dan, Guolin Zhou, Lev Becker* and Yamuna Krishnan*
Nature chemical biology 15.12 (2019): 1165-1172.
Obesity and insulin resistance promote atherosclerosis through an IFng-regulated macrophage protein network.
Catherine A. Reardon, Amulya Lingaraju, Kelly Q. Schoenfelt, Guolin Zhou, Chang Cui, Ilona Babenko, Andrew Hoofnagle, Tomas Vaisar, and Lev Becker*
Cell reports 23.10 (2018): 3021-3030.
Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity
Brittney R. Coats, Kelly Q. Schoenfelt, Valéria C. Barbosa-Lorenzi, Eduard Peris, Chang Cui, Alexandria Hoffman, Guolin Zhou, Sully Fernandez, Lijie Zhai, Ben A. Hall, Abigail S. Haka, Ajay M. Shah, Catherine A. Reardon, Matthew J. Brady, Christopher Rhodes, Frederick R. Maxfield, and Lev Becker*
Cell reports 20.13 (2017): 3149-3161.
Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages
Mario Kratz, Brittney R. Coats, Katherine B. Hisert, Derek Hagman, Vesco Mutskov, Eduard Peris, Kelly Q. Schoenfelt, Jessica N. Kuzma, Ilona Larson, Peter S. Billing, Robert W. Landerholm, Matthew Crouthamel, David Gozal, Seungmin Hwang, Pradeep K. Singh, and Lev Becker*
Cell metabolism 20.4 (2014): 614-625.