Lineage Reversion Drives WNT Independence in Intestinal Cancer

Abstract

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. This article is highlighted in the In This Issue feature, p. 1426

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

“…Surprisingly, this resembles the transcriptional profile of fetal intestine spheroids [48], which we found to be recapitulated in human BRAF V600Emutant CRC samples. Recently deposited work implicated the YAP/TAZ pathway in the induction of the fetal signature of organoids expressing an RSPO3 fusion oncoprotein along with KRAS G12D and loss of p53 [17]. Interestingly, we also observed a marked upregulation of several members of the Hippo target gene signature [80] in COL organoids, even by BRAF V600E alone ( Supplementary Fig.…”

“…In addition, BRAFmutant CRCs display aberrant WNT-pathway activity. For example, increased nuclear β-catenin localization and WNT target gene expression have been observed during tumor progression in BRAF V600E knock-in mice [6,16], while WNT signaling promoting alterations, e.g, RNF43 mutations or RSPO3 fusions, have been recently detected in BRAF V600E -mutant human CRCs [17][18][19][20].…”

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

“…Moreover, a recent study in compound mutant organoids, with Rspo3 -fusions and Kras / Braf , Trp53 , and Smad4 mutations, implicated YAP/TAZ foetal reprogramming and lineage reversion in the acquisition of resistance to Wnt-targeted therapy. Significantly, emergent organoids were addicted to YAP/TAZ signalling and were sensitive to YAP/TAZ inhibition 74 . Encouragingly, foetal-like colonic BA tumour epithelium also maintains a dependence on therapeutically targetable, microenvironmental-derived inflammatory factors, such as PGE2.…”

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

“…From a therapeutic standpoint, the acquisition of a YAP/TAZ-dependent foetal-like signature reportedly underpins resistance to Wnt-targeted therapy. To recapitulate the CRC mutational landscape, Han and colleagues [ 163 ] generated mouse colonic organoids harbouring oncogenic Ptprk - Rspo3 fusions, Kras G12D or Braf V600E , and loss-of-function mutations in the tumour-suppressor genes p53 and Smad4 . Transient exposure of these organoids to TGFβ, intended to select for Smad4 -mutant lines, conferred resistance to PORCN inhibition, signifying that the emergent organoids had lost their dependence on Wnt signalling.…”

“…Transient exposure of these organoids to TGFβ, intended to select for Smad4 -mutant lines, conferred resistance to PORCN inhibition, signifying that the emergent organoids had lost their dependence on Wnt signalling. Similarly to the regenerating epithelium, this WNT-independent growth is associated with YAP/TAZ-dependent transcriptional reprogramming and reversion to a foetal-like state, which crucially retains sensitivity to YAP/TAZ inhibition [ 163 ].…”