Abstract
In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.
Highlights
In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells
We identified MEK inhibitors as potent activators of the canonical Wnt pathway in different CRC cell lines by high-throughput compound screens and confirmed this observation across many models of normal and transformed intestinal cells
Using isogenic cell lines generated by CRISPR/Cas[9], we show that APC truncation can strongly enhance the Wnt activating effect of MEK1/2 inhibitors
Summary
In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. Wnt levels are heterogeneously distributed in CRC tissues and can dynamically fluctuate within a population of cancer cells, despite the presence of the same APC mutations[6] These observations were recently integrated into a revised model of stem cell plasticity which proposes that cancer cells can dynamically shift between a differentiated and a stemlike state[7]. Genetic alteration of the Wnt pathway component LGR58,9 or the transcription factor HOXA510 can activate stem cell plasticity in CRC Beyond these cell intrinsic signals, secreted cues from myofibroblasts in the microenvironment can modulate Wnt activity and restore cancer stemness[6]. We identified MEK inhibitors as potent activators of the canonical Wnt pathway in different CRC cell lines by high-throughput compound screens and confirmed this observation across many models of normal and transformed intestinal cells. We provide evidence that a clinically used MEK inhibitor affects cellular plasticity and induces an intestinal stem cell signature in patient-derived cancer organoids that is predictive of disease relapse
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