Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model

Degirmenci, Bahar; Dinçer, Cansu; Demirel, Habibe Cansu; Berková, Linda; Moor, Andreas E.; Kahraman, Abdullah; Hausmann, George; Aguet, Michel; Tunçbağ, Nurcan; Valenta, Tomáš; Basler, Konrad

doi:10.1016/j.isci.2021.103369

Cited by 5 publications

(5 citation statements)

References 49 publications

(71 reference statements)

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“…Here, the expression of Wnt7a/Wnt7b was upregulated in tumor cells compared to a healthy colon. In this model, blockage of WNT secretion from tumor cells by conditional knockout of Wls / Gpr177 increased the proportion of apoptotic and differentiated tumor cells, highlighting the importance of endogenous WNT secretion to maintain self-renewing capacity [ 120 ]. Furthermore, WNTs derived from the tumor microenvironment can contribute to cancer cell stemness, and co-culture of ovarian cancer stem cells with M2-polarized macrophages increased the expression of the stem cell marker ALDH in the cancer cells, an effect which could be reversed by blockade of WNT secretion, as well as knockdown of WNT5B in macrophages [ 121 ].…”

Section: Secreted Wnts In Cancer Stemnessmentioning

confidence: 99%

“…Small molecules inhibiting Porcupine, e.g., LGK-974, block general secretion of WNTs and are the most intensively studied antineoplastic drugs that target the WNT pathway. This class of drugs proved to effectively inhibit canonical Wnt signaling and to induce cancer cell death and slow tumor growth in preclinical animal models [ 120 , 188 , 189 , 190 , 191 , 192 ]. For instance, in HNSCC xenograft models, LGK-974 treatment strongly reduced Wnt target gene expression and tumor volume, in the absence of obvious adverse effects [ 190 ].…”

Section: Therapeutical Targeting Of Wnts In Cancermentioning

confidence: 99%

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The Roles of Secreted Wnt Ligands in Cancer

Werner

Boonekamp

Zhan

et al. 2023

IJMS

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Wnt ligands are secreted signaling proteins that display a wide range of biological effects. They play key roles in stimulating Wnt signaling pathways to facilitate processes such as tissue homeostasis and regeneration. Dysregulation of Wnt signaling is a hallmark of many cancers and genetic alterations in various Wnt signaling components, which result in ligand-independent or ligand-dependent hyperactivation of the pathway that have been identified. Recently, research is focusing on the impact of Wnt signaling on the interaction between tumor cells and their micro-environment. This Wnt-mediated crosstalk can act either in a tumor promoting or suppressing fashion. In this review, we comprehensively outline the function of Wnt ligands in different tumor entities and their impact on key phenotypes, including cancer stemness, drug resistance, metastasis, and immune evasion. Lastly, we elaborate approaches to target Wnt ligands in cancer therapy.

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Section: Secreted Wnts In Cancer Stemnessmentioning

confidence: 99%

Section: Therapeutical Targeting Of Wnts In Cancermentioning

confidence: 99%

The Roles of Secreted Wnt Ligands in Cancer

Werner

Boonekamp

Zhan

et al. 2023

IJMS

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“…However, as most of these mutations induce Wnt signalling downstream of Wnt secretion, the regulation of Wnt export is not usually considered to be a relevant treatment option, although colon cancer cells secrete and respond to Wnt ligands ( Voloshanenko et al, 2013 ). A recent publication described a subset of human colon cancer cases without mutations in core Wnt components and a respective mouse model that required autosecreted Wnts for survival ( Degirmenci et al, 2021 ). Furthermore, another subset of colon cancers with mutations in RNF43/ZNRF3 or R-spondins 2/3 require secreted Wnts for proliferation ( Flanagan et al, 2022 ).…”

Section: Wnt Export Organ Development and Diseasementioning

confidence: 99%

The role of Evi/Wntless in exporting Wnt proteins

Wolf

Boutros

2023

Development

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Intercellular communication by Wnt proteins governs many essential processes during development, tissue homeostasis and disease in all metazoans. Many context-dependent effects are initiated in the Wnt-producing cells and depend on the export of lipidated Wnt proteins. Although much focus has been on understanding intracellular Wnt signal transduction, the cellular machinery responsible for Wnt secretion became better understood only recently. After lipid modification by the acyl-transferase Porcupine, Wnt proteins bind their dedicated cargo protein Evi/Wntless for transport and secretion. Evi/Wntless and Porcupine are conserved transmembrane proteins, and their 3D structures were recently determined. In this Review, we summarise studies and structural data highlighting how Wnts are transported from the ER to the plasma membrane, and the role of SNX3-retromer during the recycling of its cargo receptor Evi/Wntless. We also describe the regulation of Wnt export through a post-translational mechanism and review the importance of Wnt secretion for organ development and cancer, and as a future biomarker.

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“…27 It is thought to preserve cancer stemness, protect tumor cells from immunosurveillance, foster secondary tumor growth, and drive cancer metastasis. [28][29][30][31] The Wnt signaling pathway (Fig. 2) is either in "on" or "off" mode in normal colonic crypts.…”

Section: Regulating Intestinal Epithelial Cell Fatementioning

confidence: 99%

“…Although integral to normal physiological cellular proliferation, hyperactivation of the Wnt pathway has a substantial role and is almost universal in all types of CRC 27 . It is thought to preserve cancer stemness, protect tumor cells from immunosurveillance, foster secondary tumor growth, and drive cancer metastasis 28–31 …”

Section: Regulating Intestinal Epithelial Cell Fatementioning

confidence: 99%

The emerging era of personalized medicine in advanced colorectal cancer

Reid

Leedham

et al. 2022

J of Gastro and Hepatol

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Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre‐clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.

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Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model

Cited by 5 publications

References 49 publications

The Roles of Secreted Wnt Ligands in Cancer

The Roles of Secreted Wnt Ligands in Cancer

The role of Evi/Wntless in exporting Wnt proteins

The emerging era of personalized medicine in advanced colorectal cancer

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