Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer
Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mu...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/11/3355 |
| _version_ | 1797548037894045696 |
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| author | Sam O. Kleeman Simon J. Leedham |
| author_facet | Sam O. Kleeman Simon J. Leedham |
| author_sort | Sam O. Kleeman |
| collection | DOAJ |
| description | Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer. |
| first_indexed | 2024-03-10T14:52:42Z |
| format | Article |
| id | doaj.art-4174b7fbdaf045d6a29494974f029644 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T14:52:42Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4174b7fbdaf045d6a29494974f0296442023-11-20T20:48:42ZengMDPI AGCancers2072-66942020-11-011211335510.3390/cancers12113355Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal CancerSam O. Kleeman0Simon J. Leedham1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USAIntestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford OX3 7BN, UKWnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer.https://www.mdpi.com/2072-6694/12/11/3355WntsignalingcolorectalcancerporcupineR-spondin |
| spellingShingle | Sam O. Kleeman Simon J. Leedham Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer Cancers Wnt signaling colorectal cancer porcupine R-spondin |
| title | Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer |
| title_full | Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer |
| title_fullStr | Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer |
| title_full_unstemmed | Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer |
| title_short | Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer |
| title_sort | not all wnt activation is equal ligand dependent versus ligand independent wnt activation in colorectal cancer |
| topic | Wnt signaling colorectal cancer porcupine R-spondin |
| url | https://www.mdpi.com/2072-6694/12/11/3355 |
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