Stewart Kim

All Publications

• EML4-ALK variant-specific genetic interactions shape lung tumorigenesis. Cancer discovery Diaz-Jimenez, A., Shuldiner, E. G., Somogyi, K., Shih, K., Gonzalez-Velasco, O., Najajreh, M., Kim, S., Akkas, F., Murray, C. W., Andrejka, L., Tsai, M. K., Brors, B., Hofmann, I., Sivakumar, S., Sisoudiya, S. D., Sokol, E. S., Cai, H., Petrov, D. A., Winslow, M. M., Sotillo, R. 2025

  Abstract

  Diverse fusions of EML4 and ALK are oncogenic drivers in lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. Here, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes rather than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion-driven cancers.

  View details for DOI 10.1158/2159-8290.CD-24-1417

  View details for PubMedID 40986428

• Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis. Nature Neuhofer, P., Roake, C. M., Kim, S. J., Lu, R. J., West, R. B., Charville, G. W., Artandi, S. E. 2021

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide1. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development2,3. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERThigh acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERThigh acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras-MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERThigh acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.

  View details for DOI 10.1038/s41586-021-03916-2

  View details for PubMedID 34526722