The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway
Abstract Background Colorectal cancer (CRC) remains largely incurable when diagnosed at the metastatic stage. Despite some advances in precision medicine for this disease in recent years, new molecular targets, as well as prognostic/predictive markers, are highly needed. Neuroligin 1 (NLGN1) is a tr...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-09-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02465-4 |
| _version_ | 1798032546470035456 |
|---|---|
| author | Margherita Pergolizzi Laura Bizzozero Federica Maione Elena Maldi Claudio Isella Marco Macagno Elisa Mariella Alberto Bardelli Enzo Medico Caterina Marchiò Guido Serini Federica Di Nicolantonio Federico Bussolino Marco Arese |
| author_facet | Margherita Pergolizzi Laura Bizzozero Federica Maione Elena Maldi Claudio Isella Marco Macagno Elisa Mariella Alberto Bardelli Enzo Medico Caterina Marchiò Guido Serini Federica Di Nicolantonio Federico Bussolino Marco Arese |
| author_sort | Margherita Pergolizzi |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer (CRC) remains largely incurable when diagnosed at the metastatic stage. Despite some advances in precision medicine for this disease in recent years, new molecular targets, as well as prognostic/predictive markers, are highly needed. Neuroligin 1 (NLGN1) is a transmembrane protein that interacts at the synapse with the tumor suppressor adenomatous polyposis Coli (APC), which is heavily involved in the pathogenesis of CRC and is a key player in the WNT/β-catenin pathway. Methods After performing expression studies of NLGN1 on human CRC samples, in this paper we used in vitro and in vivo approaches to study CRC cells extravasation and metastasis formation capabilities. At the molecular level, the functional link between APC and NLGN1 in the cancer context was studied. Results Here we show that NLGN1 is expressed in human colorectal tumors, including clusters of aggressive migrating (budding) single tumor cells and vascular emboli. We found that NLGN1 promotes CRC cells crossing of an endothelial monolayer (i.e. Trans-Endothelial Migration or TEM) in vitro, as well as cell extravasation/lung invasion and differential organ metastatization in two mouse models. Mechanistically, NLGN1 promotes APC localization to the cell membrane and co-immunoprecipitates with some isoforms of this protein stimulates β-catenin translocation to the nucleus, upregulates mesenchymal markers and WNT target genes and induces an “EMT phenotype” in CRC cell lines Conclusions In conclusion, we have uncovered a novel modulator of CRC aggressiveness which impacts on a critical pathogenetic pathway of this disease, and may represent a novel therapeutic target, with the added benefit of carrying over substantial knowledge from the neurobiology field. |
| first_indexed | 2024-04-11T20:15:47Z |
| format | Article |
| id | doaj.art-48b8b8cf40af4fdfafe76959cde02cec |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-11T20:15:47Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-48b8b8cf40af4fdfafe76959cde02cec2022-12-22T04:04:59ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-09-0141111610.1186/s13046-022-02465-4The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathwayMargherita Pergolizzi0Laura Bizzozero1Federica Maione2Elena Maldi3Claudio Isella4Marco Macagno5Elisa Mariella6Alberto Bardelli7Enzo Medico8Caterina Marchiò9Guido Serini10Federica Di Nicolantonio11Federico Bussolino12Marco Arese13Department of Oncology, University of TorinoDepartment of Oncology, University of TorinoDepartment of Oncology, University of TorinoPathology Unit, Candiolo Cancer Institute, FPO-IRCCSDepartment of Oncology, University of TorinoCandiolo Cancer Institute, FPO-IRCCSDepartment of Oncology, University of TorinoDepartment of Oncology, University of TorinoDepartment of Oncology, University of TorinoPathology Unit, Candiolo Cancer Institute, FPO-IRCCSDepartment of Oncology, University of TorinoDepartment of Oncology, University of TorinoDepartment of Oncology, University of TorinoDepartment of Oncology, University of TorinoAbstract Background Colorectal cancer (CRC) remains largely incurable when diagnosed at the metastatic stage. Despite some advances in precision medicine for this disease in recent years, new molecular targets, as well as prognostic/predictive markers, are highly needed. Neuroligin 1 (NLGN1) is a transmembrane protein that interacts at the synapse with the tumor suppressor adenomatous polyposis Coli (APC), which is heavily involved in the pathogenesis of CRC and is a key player in the WNT/β-catenin pathway. Methods After performing expression studies of NLGN1 on human CRC samples, in this paper we used in vitro and in vivo approaches to study CRC cells extravasation and metastasis formation capabilities. At the molecular level, the functional link between APC and NLGN1 in the cancer context was studied. Results Here we show that NLGN1 is expressed in human colorectal tumors, including clusters of aggressive migrating (budding) single tumor cells and vascular emboli. We found that NLGN1 promotes CRC cells crossing of an endothelial monolayer (i.e. Trans-Endothelial Migration or TEM) in vitro, as well as cell extravasation/lung invasion and differential organ metastatization in two mouse models. Mechanistically, NLGN1 promotes APC localization to the cell membrane and co-immunoprecipitates with some isoforms of this protein stimulates β-catenin translocation to the nucleus, upregulates mesenchymal markers and WNT target genes and induces an “EMT phenotype” in CRC cell lines Conclusions In conclusion, we have uncovered a novel modulator of CRC aggressiveness which impacts on a critical pathogenetic pathway of this disease, and may represent a novel therapeutic target, with the added benefit of carrying over substantial knowledge from the neurobiology field.https://doi.org/10.1186/s13046-022-02465-4Neuroligin 1tumor buddingintravasation/extravasationAPCmetastasisWNT pathway |
| spellingShingle | Margherita Pergolizzi Laura Bizzozero Federica Maione Elena Maldi Claudio Isella Marco Macagno Elisa Mariella Alberto Bardelli Enzo Medico Caterina Marchiò Guido Serini Federica Di Nicolantonio Federico Bussolino Marco Arese The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway Journal of Experimental & Clinical Cancer Research Neuroligin 1 tumor budding intravasation/extravasation APC metastasis WNT pathway |
| title | The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway |
| title_full | The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway |
| title_fullStr | The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway |
| title_full_unstemmed | The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway |
| title_short | The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway |
| title_sort | neuronal protein neuroligin 1 promotes colorectal cancer progression by modulating the apc β catenin pathway |
| topic | Neuroligin 1 tumor budding intravasation/extravasation APC metastasis WNT pathway |
| url | https://doi.org/10.1186/s13046-022-02465-4 |
| work_keys_str_mv | AT margheritapergolizzi theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT laurabizzozero theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT federicamaione theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT elenamaldi theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT claudioisella theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT marcomacagno theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT elisamariella theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT albertobardelli theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT enzomedico theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT caterinamarchio theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT guidoserini theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT federicadinicolantonio theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT federicobussolino theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT marcoarese theneuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT margheritapergolizzi neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT laurabizzozero neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT federicamaione neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT elenamaldi neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT claudioisella neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT marcomacagno neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT elisamariella neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT albertobardelli neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT enzomedico neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT caterinamarchio neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT guidoserini neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT federicadinicolantonio neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT federicobussolino neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway AT marcoarese neuronalproteinneuroligin1promotescolorectalcancerprogressionbymodulatingtheapcbcateninpathway |