All Publications

  • High-Throughput Identification, Modeling, and Analysis of Cancer Driver Genes In Vivo. Cold Spring Harbor perspectives in medicine Tang, Y. J., Shuldiner, E. G., Karmakar, S., Winslow, M. M. 2023


    The vast number of genomic and molecular alterations in cancer pose a substantial challenge to uncovering the mechanisms of tumorigenesis and identifying therapeutic targets. High-throughput functional genomic methods in genetically engineered mouse models allow for rapid and systematic investigation of cancer driver genes. In this review, we discuss the basic concepts and tools for multiplexed investigation of functionally important cancer genes in vivo using autochthonous cancer models. Furthermore, we highlight emerging technical advances in the field, potential opportunities for future investigation, and outline a vision for integrating multiplexed genetic perturbations with detailed molecular analyses to advance our understanding of the genetic and molecular basis of cancer.

    View details for DOI 10.1101/cshperspect.a041382

    View details for PubMedID 37277208

  • Dissecting the role of Stag2 in lung adenocarcinoma Ashkin, E. L., Cai, H., Tang, Y. J., Li, C., Chew, S., Hung, K., Belk, J., Karmakar, S., Hebert, J., Yousefi, M., Swanton, C., Petrov, D. A., Winslow, M. AMER ASSOC CANCER RESEARCH. 2022
  • Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities. Cancer research Yousefi, M., Boross, G., Weiss, C., Murray, C. W., Hebert, J. D., Cai, H., Ashkin, E. L., Karmakar, S., Andrejka, L., Chen, L., Wang, M., Tsai, M. K., Lin, W., Li, C., Yakhchalian, P., Colon, C. I., Chew, S., Chu, P., Swanton, C., Kunder, C. A., Petrov, D. A., Winslow, M. M. 2022; 82 (8): 1589-1602


    Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type, and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Generation of hundreds of diverse combinations of tumor suppressor alterations demonstrates that inactivation of suppressors of the RAS and PI3K pathways drives the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common feature of an event in oncogene-negative human lung adenocarcinomas. These Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacologic inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma.SIGNIFICANCE: To address the large fraction of lung adenocarcinomas lacking mutations in proto-oncogenes for which targeted therapies are unavailable, this work uncovers driver pathways of oncogene-negative lung adenocarcinomas and demonstrates their therapeutic vulnerabilities.

    View details for DOI 10.1158/0008-5472.CAN-22-0059

    View details for PubMedID 35425962