Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells
Summary: 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. T...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-12-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717316455 |
| _version_ | 1818034391888166912 |
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| author | Joseph L. Regan Dirk Schumacher Stephanie Staudte Andreas Steffen Johannes Haybaeck Ulrich Keilholz Caroline Schweiger Nicole Golob-Schwarzl Dominik Mumberg David Henderson Hans Lehrach Christian R.A. Regenbrecht Reinhold Schäfer Martin Lange |
| author_facet | Joseph L. Regan Dirk Schumacher Stephanie Staudte Andreas Steffen Johannes Haybaeck Ulrich Keilholz Caroline Schweiger Nicole Golob-Schwarzl Dominik Mumberg David Henderson Hans Lehrach Christian R.A. Regenbrecht Reinhold Schäfer Martin Lange |
| author_sort | Joseph L. Regan |
| collection | DOAJ |
| description | Summary: 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. : 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 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 |
| first_indexed | 2024-12-10T06:38:25Z |
| format | Article |
| id | doaj.art-0bc975435f724fe6953131af21245493 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T06:38:25Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-0bc975435f724fe6953131af212454932022-12-22T01:58:51ZengElsevierCell Reports2211-12472017-12-01211028132828Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem CellsJoseph L. Regan0Dirk Schumacher1Stephanie Staudte2Andreas Steffen3Johannes Haybaeck4Ulrich Keilholz5Caroline Schweiger6Nicole Golob-Schwarzl7Dominik Mumberg8David Henderson9Hans Lehrach10Christian R.A. Regenbrecht11Reinhold Schäfer12Martin Lange13Bayer AG, Drug Discovery, Pharmaceuticals, 13342 Berlin, Germany; Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Corresponding authorLaboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; German Cancer Consortium (DKTK), DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyBayer AG, Drug Discovery, Pharmaceuticals, 13342 Berlin, Germany; Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyBayer AG, Drug Discovery, Pharmaceuticals, 13342 Berlin, GermanyDepartment of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, Leipziger Straße 44, Haus 28, 39120 Magdeburg, Germany; Institute of Pathology, Medical University Graz, Auenbruggerplatz 25, 8036 Graz, AustriaCharité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyInstitute of Pathology, Medical University Graz, Auenbruggerplatz 25, 8036 Graz, AustriaInstitute of Pathology, Medical University Graz, Auenbruggerplatz 25, 8036 Graz, AustriaBayer AG, Drug Discovery, Pharmaceuticals, 13342 Berlin, GermanyBayer AG, Drug Discovery, Pharmaceuticals, 13342 Berlin, GermanyMax Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, GermanyCharité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; cpo – cellular phenomics & oncology Berlin-Buch GmbH, Robert-Rössle-Straße 10, 13125 Berlin, GermanyCharité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; German Cancer Consortium (DKTK), DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyBayer AG, Drug Discovery, Pharmaceuticals, 13342 Berlin, Germany; Corresponding authorSummary: 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. : 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 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, SHHhttp://www.sciencedirect.com/science/article/pii/S2211124717316455 |
| spellingShingle | Joseph L. Regan Dirk Schumacher Stephanie Staudte Andreas Steffen Johannes Haybaeck Ulrich Keilholz Caroline Schweiger Nicole Golob-Schwarzl Dominik Mumberg David Henderson Hans Lehrach Christian R.A. Regenbrecht Reinhold Schäfer Martin Lange 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 |
| title | Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells |
| title_full | Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells |
| title_fullStr | Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells |
| title_full_unstemmed | Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells |
| title_short | Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells |
| title_sort | non canonical hedgehog signaling is a positive regulator of the wnt pathway and is required for the survival of colon cancer stem cells |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717316455 |
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