Project Summary Research Aneuploidy, the gain or loss of whole chromosomes or chromosome arms, is a near-universal feature of cancer. However, the role of aneuploidy in tumor pathogenesis remains an unanswered question in cancer biology. Lung squamous cell carcinomas (SCCs) have a high rate of aneuploidy when compared to other tumor types. For lung SCC, unlike lung adenocarcinoma, few targeted therapies are currently available, as there are fewer oncogenic mutations identified in lung SCCs. However, SCCs are characterized by a distinct profile of aneuploidy events. In particular, chromosome arm 3p is lost in almost 80% of lung SCCs, suggesting it plays an important role in oncogenesis in this tumor type and may be a useful disease target. The goal of this proposal is to understand the phenotypic effects of chromosome 3p deletion and whether cancer cells with this alteration can be specifically targeted. We have previously developed a genome engineering approach to delete chromosome arm 3p in human lung epithelial cells. Following on with this model system, three complimentary approaches will be pursued in this proposal: (1) study of interferon signaling up-regulated in chromosome 3p deleted cells, (2) identification of adaptive mechanisms cells use to overcome proliferation defects induced by chromosome 3p deletion, and (3) systematic genetic screening to identify dependencies specific to chromosome 3p deletion. By determining the effect of chromosome 3p loss in lung cells, we will gain insights into how a patient-specific aneuploidy contributes to tumor development. These studies may also identify novel therapeutic targets for treatment of SCCs. Candidate Career Goals My long-term goal is to understand the role of aneuploidy and chromosome imbalance in cancer development. As an independent investigator, I want to build my research program on cancer cell biology and analysis of patient data, combining experimental and computational approaches to study aneuploidy. The K22 award will allow me to obtain additional training from computational biologists and other collaborators to perform the proposed experiments as an independent investigator. Environment The Dana-Farber Cancer Institute has internationally recognized research programs in both basic and translational research, including immuno-oncology and cancer genomics. In addition, as an affiliated researcher of the Broad Institute, I will have access to genome sequencing services and high-throughput screening services they provide. I expect to obtain a faculty position in a research institution that has similar facilities and intellectual environment as these institutions. After obtaining a tenure-track faculty position, I will put together an advisory committee of cancer researchers to oversee my career development.