Lineage reversion drives WNT independence in intestinal cancer.

TitleLineage reversion drives WNT independence in intestinal cancer.
Publication TypeJournal Article
Year of Publication2020
AuthorsHan T, Goswami S, Hu Y, Tang F, Zafra MPaz, Murphy C, Cao Z, Poirier JT, Khurana E, Elemento O, Hechtman JF, Ganesh K, Yaeger R, Dow LE
JournalCancer Discov
Date Published2020 Jun 16

The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFB 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 CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.

Alternate JournalCancer Discov
PubMed ID32546576
Grant ListK08 CA230213 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
T32 CA203702 / CA / NCI NIH HHS / United States