Cancer cells reside in a complex microenvironment and interact with many stromal and immune cell components. During tumorigenesis, highly reactive oxygen species (ROS) accumulate due to increased basal metabolic activity, mitochondrial dysfunction, uncontrolled cytokine signaling, and deregulation of genes that control redox signaling. The resulting oxidative stress promotes tumor initiation and progression, and increasing evidence suggests a role for oxidative stress in signaling to the immune system. However, little is known how the generation and modulation of ROS within the tumor can impact the interplay between the tumor cell and the microenvironment.
Our laboratory would like to explore how such tumor intrinsic factors impact immune cell infiltration and influence response to immunotherapy. To this end, we perform functional genomics to interrogate the role of clinically relevant oncogenes and tumor suppressors on the tumor metabolic environment and subsequent impact on immune function. Understanding such causal factors should enable new therapeutic approaches that may facilitate beneficial immune infiltrates into tumors and expand the fraction of patients capable of responding to novel immunotherapies.
Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi Screening. McDonald ER 3rd*, de Weck A*, Schlabach MR*, Billy E*, Mavrakis KJ*, Hoffman GR*, Belur D, Castelletti D, Frias E, Gampa K, Golji J, Kao I, Li L, Megel P, Perkins TA, Ramadan N, Ruddy DA, Silver SJ, Sovath S, Stump M, Weber O, Widmer R, Yu J, Yu K, Yue Y, Abramowski D, Ackley E, Barrett R, Berger J, Bernard JL, Billig R, Brachmann SM, Buxton F, Caothien R, Caushi JX, Chung FS, Cortés-Cros M, deBeaumont RS, Delaunay C, Desplat A, Duong W, Dwoske DA, Eldridge RS, Farsidjani A, Feng F, Feng J, Flemming D, Forrester W, Galli GG, Gao Z, Gauter F, Gibaja V, Haas K, Hattenberger M, Hood T, Hurov KE, Jagani Z, Jenal M, Johnson JA, Jones MD, Kapoor A, Korn J, Liu J, Liu Q, Liu S, Liu Y, Loo AT, Macchi KJ, Martin T, McAllister G, Meyer A, Mollé S, Pagliarini RA, Phadke T, Repko B, Schouwey T, Shanahan F, Shen Q, Stamm C, Stephan C, Stucke VM, Tiedt R, Varadarajan M, Venkatesan K, Vitari AC, Wallroth M, Weiler J, Zhang J, Mickanin C, Myer VE, Porter JA, Lai A, Bitter H, Lees E, Keen N, Kauffmann A, Stegmeier F, Hofmann F, Schmelzle T, Sellers WR. *=co-first author Cell 2017 Jul 27;170(3):577-592.
Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Mavrakis KJ, McDonald ER 3rd, Schlabach MR, Billy E, Hoffman GR, deWeck A, Ruddy DA, Venkatesan K, Yu J, McAllister G, Stump M, deBeaumont R, Ho S, Yue Y, Liu Y, Yan-Neale Y, Yang G, Lin F, Yin H, Gao H, Kipp DR, Zhao S, McNamara JT, Sprague ER, Zheng B, Lin Y, Cho YS, Gu J, Crawford K, Ciccone D, Vitari AC, Lai A, Capka V, Hurov K, Porter JA, Tallarico J, Mickanin C, Lees E, Pagliarini R, Keen N, Schmelzle T, Hofmann F, Stegmeier F, Sellers WR. Science 2016 Mar 11;351(6278)