Functional Genomics and Cell Biology of Macrophages

Macrophages are immune cells that maintain the homeostasis of all tissues by eliminating more than 200 billion damaged or senescent cells every day via phagocytosis. As we age, however, aberrant cells accumulate and give rise to a wide range of diseases including cancer, neurodegeneration, and atherosclerosis. Why macrophages fail to clear unwanted cells in the context of age-related diseases is not known. 

Despite our incomplete knowledge, therapies have been developed that can be used to treat disease by stimulating macrophages to precisely eliminate specific cell populations from the body. These therapies have transformed treatment outcomes in some diseases, including certain autoimmune diseases and a subset of lymphomas. However, the potential of macrophages as engineered cell therapies remains largely untapped.

Our work is driven equally by curiosity about the diverse forms and functions of phagocytosis in nature and a motivation to enable new treatments for people suffering from incurable diseases. Some of the questions we are interested in are:

• What mechanisms do macrophages use to discern between healthy and abnormal cells when making all-or-none decisions about target cell destruction?

• What are the barriers to effective macrophage-mediated clearance of cancer cells in primary tumors and metastatic sites?

• How can we systematically engineer macrophages to robustly eliminate a wide range of disease-causing cells?

• Why does macrophage clearance capacity decline with age, and can this be reversed?

To answer these questions, we develop powerful genetic screening approaches to discover molecules that regulate macrophage function and apply biochemical, cell biological, and in vivo experiments to understand how these components work at a mechanistic level. We are particularly interested in genes, metabolites, and processes that have not been studied before and which may point us to entirely new avenues for disease intervention. 

Vorselen, D.*, Kamber, R.A.*, Labitigan, R.L.D., van Loon, A.P., Peterman, E., Delgado, M.K., Lin, S., Rasmussen, J.P., Bassik, M.C.#, Theriot, J.A#. Cell surface receptors TREM2, CD14 and integrin αMβ2 drive sinking engulfment in phosphatidylserine-mediated phagocytosis. bioRxiv (2022).

Kamber, R.A., Nishiga, Y., Morton, B., Banuelos, A.M., Barkal, A.M., Vences-Catalan, F., Gu, M., Fernandez, D, Seoane, J.A., Yao, D., Liu, K., Lin, S., Spees, K, Curtis, C., Jerby-Arnon, L., Weissman, I.L., Sage, J., Bassik, M.C., 2021. Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis. Nature, 597(7877), pp.549-554.

Wainberg, M.*, Kamber, R.A.*, Balsubramani, A.*, Meyers, R.M., Sinnott-Armstrong, N., Hornburg, D., Jiang, L., Chan, J., Jian, R., Gu, M., Shcherbina, A., Dubreuil, M.M., Meuleman, W., Spees, K., Snyder, M.P., Bassik, M.C., Kundaje, A., 2021. A genome-wide atlas of co-essential modules assigns function to uncharacterized genes. Nature Genetics, 53(5), pp.638-649.

Kamber, R.A.*, Shoemaker, C.J.* and Denic, V., 2015. Receptor-bound targets of selective autophagy use a scaffold protein to activate the Atg1 kinase. Molecular Cell, 59(3), pp.372-381.