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

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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Summary: Colon cancer is a heterogeneous tumor driven by a subpopulation of Moss Wall Art 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.: Colon cancer is a heterogeneous tumor driven by a subpopulation(s) of therapy-resistant cancer stem cells (CSCs).Regan et al.

use 3D culture models to demonstrate that CSC survival is regulated ARGININE by non-canonical, SHH-dependent, PTCH1-dependent Hedgehog signaling, which acts as a positive regulator of WNT signaling to block CSC differentiation.Keywords: WNT pathway, non-canonical Hedgehog signaling, cancer stem cell, colon cancer, cancer organoid, PTCH1, HHAT, SHH.