GATA6 Maintains Adenoma Stem Cells via Suppression of BMP Signaling

Development of precancerous adenomas through activation of the WNT pathway or inactivation of bone morphogenetic protein (BMP) signaling is the precursor for the development of colorectal cancer. Recent evidence suggests that adenomas harbor a population of stem cells (AdSC) that self-renew and give rise to adenoma lineages similar to normal intestinal stem cells (ISC). Whissell and colleagues discovered a role for the transcription factor GATA6 in regulating AdSCs and suppressing the BMP signaling pathway. Depletion and overexpression of GATA6 in colorectal cancer cell lines confirmed that GATA6 drives expression of the AdSC/ISC marker leucine-rich repeat containing G protein-coupled receptor 5 (LGR5). Conditional knockout of Gata6 in ISCs resulted in decreased tumor burden and diminished mortality, suggesting that GATA6 promotes colon tumorigenesis. Gata6-deficient adenomas harbored a reduced frequency of LGR5⁺ AdSCs that were restricted to the lowest positions of adenoma glands and displayed upregulation of BMP target genes and nuclear accumulation of phosphorylated SMADs in AdSCs, consistent with the role of BMP signaling in suppressing intestinal tumor formation. Similarly, Gata6-deficient adenoma organoid cultures exhibited an increase in BMP pathway components and decreased organoid growth, indicative of impaired AdSC self-renewal. Inhibitors of BMP signaling rescued the proliferative and clonogenic potential of Gata6-deficient tumor organoids. Moreover, treatment of mice with pharmacologic BMP inhibitors increased tumor burden and rescued the Gata6-deficient phenotype, suggesting a direct role of GATA6 in enhancing adenoma formation through disruption of BMP signaling. In support of this idea, GATA6 competed with β-catenin/T-cell factor 4 (TCF4, also known as TCF7L2) for binding to a distal enhancer region of BMP4 that contains a SNP linked to colorectal cancer susceptibility, and regulated the expression of many β-catenin/TCF4 targets. Together, these findings demonstrate that GATA6 may play a crucial role in establishing an environment that facilitates colorectal cancer initiation.

Whissell G, Montagni E, Martinelli P, Hernando-Momblona X, Sevillano M, Jung P, et al. The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression. Nat Cell Biol 2014;16:695–707.

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