Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and 
Is Required for the Survival of Colon Cancer Stem Cells

Regan, J. L.; Schumacher, D.; Staudte, S.; Steffen, A.; Haybaeck, J.; Keilholz, U.; Schweiger, C.; Golob-Schwarzl, N.; Mumberg, D.; Henderson, D.; Lehrach, H.; Regenbrecht, C. R. A.; Schafer, R.; Lange, M.

doi:10.1016/j.celrep.2017.11.025

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Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells

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Lehrach, H.
Emeritus Group of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Regan, J. L., Schumacher, D., Staudte, S., Steffen, A., Haybaeck, J., Keilholz, U., et al. (2017). Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells. Cell Reports, 21(10), 2813-2828. doi:10.1016/j.celrep.2017.11.025.

Cite as: https://hdl.handle.net/21.11116/0000-0000-F693-4

Abstract

Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs). To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH)-positive CSCs. Canonical GLI-dependent Hedgehog signaling is a negative regulator of WNT signaling in normal intestine and intestinal tumors. Here, we show that Hedgehog signaling in colon CSCs is autocrine SHH-dependent, non-canonical PTCH1 dependent, and GLI independent. In addition, using small-molecule inhibitors and RNAi against SHH-palmitoylating Hedgehog acyltransferase (HHAT), we demonstrate that non-canonical Hedgehog signaling is a positive regulator of WNT signaling and required for colon CSC survival.