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

Joseph L. Regan | Zendy; Dirk Schumacher | Zendy; Stephanie Staudte | Zendy; Andreas Steffen | Zendy; Johannes Haybaeck | Zendy; Ulrich Keilholz | Zendy; Caroline Schweiger | Zendy; Nicole GolobSchwarzl | Zendy; Dominik Mumberg | Zendy; David Henderson | Zendy; Hans Lehrach | Zendy; Christian Regenbrecht | Zendy; Reinhold Schäfer | Zendy; Martin Lange | Zendy

Open Access

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

Author(s) -

Joseph L. Regan,

Dirk Schumacher,

Stephanie Staudte,

Andreas Steffen,

Johannes Haybaeck,

Ulrich Keilholz,

Caroline Schweiger,

Nicole GolobSchwarzl,

Dominik Mumberg,

David Henderson,

Hans Lehrach,

Christian Regenbrecht,

Reinhold Schäfer,

Martin Lange

Publication year - 2017

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2017.11.025

Subject(s) - wnt signaling pathway , hedgehog , smoothened , biology , cancer research , cancer stem cell , hedgehog signaling pathway , patched , autocrine signalling , stem cell , cancer , gli1 , colorectal cancer , microbiology and biotechnology , signal transduction , genetics , receptor

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.

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