Lineage Reversion Drives WNT Independence in Intestinal Cancer Han, Teng Goswami, Sukanya Hu, Yang Tang, Fanying Zafra, María Paz Murphy, Charles Cao, Zhen Poirier, John T. Khurana, Ekta Elemento, Olivier Hechtman, Jaclyn F. Ganesh, Karuna Yaeger, Rona Dow, Lukas E. WNT Colorectal cancer Single cell RNA sequencing This work was supported by a Research Scholar Award from the American Cancer Society (RSG-17-202-01-TBG), a project grant from the NIH/NCI (1R01CA222517-01A1), project grants from the Starr Cancer Consortium (#I10-0095 and #I11-0040) and a Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17). Research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C. M.P. Zafra is supported in part by NCI grant NIH T32 CA203702. The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and in vivo colorectal cancer models, the accumulation of colorectal cancer-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of TP53 and SMAD4, transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent colorectal cancer growth, and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs. SIGNIFICANCE: Colorectal and intestinal cancers are driven by mutations in the WNT pathway, and drugs aimed at suppressing WNT signaling are in active clinical development. Our study identifies a mechanism of acquired resistance to WNT inhibition and highlights a potential strategy to target those drug-resistant cells 2026-01-27T12:40:01Z 2026-01-27T12:40:01Z 2020-10 journal article Han, Teng et al. Lineage Reversion Drives WNT Independence in Intestinal Cancer. Cancer Discovery . 2020;10(10):1590-1609. DOI: 10.1158/2159-8290.CD-19-1536 https://hdl.handle.net/10481/110356 10.1158/2159-8290.CD-19-1536 eng open access American Association for Cancer Research