Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation
Abstract Background Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GS...
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02497-w |
| _version_ | 1797998277755404288 |
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| author | Manuel Gámez-Chiachio Ángela Molina-Crespo Carmen Ramos-Nebot Jeannette Martinez-Val Lidia Martinez Katja Gassner Francisco J. Llobet Mario Soriano Alberto Hernandez Marco Cordani Cristina Bernadó-Morales Eva Diaz Alejandro Rojo-Sebastian Juan Carlos Triviño Laura Sanchez Ruth Rodríguez-Barrueco Joaquín Arribas David Llobet-Navás David Sarrió Gema Moreno-Bueno |
| author_facet | Manuel Gámez-Chiachio Ángela Molina-Crespo Carmen Ramos-Nebot Jeannette Martinez-Val Lidia Martinez Katja Gassner Francisco J. Llobet Mario Soriano Alberto Hernandez Marco Cordani Cristina Bernadó-Morales Eva Diaz Alejandro Rojo-Sebastian Juan Carlos Triviño Laura Sanchez Ruth Rodríguez-Barrueco Joaquín Arribas David Llobet-Navás David Sarrió Gema Moreno-Bueno |
| author_sort | Manuel Gámez-Chiachio |
| collection | DOAJ |
| description | Abstract Background Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Methods Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. Results GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Conclusion Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome. |
| first_indexed | 2024-04-11T10:46:07Z |
| format | Article |
| id | doaj.art-f27d67a436224cd7aff26d109a24a883 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-11T10:46:07Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-f27d67a436224cd7aff26d109a24a8832022-12-22T04:29:03ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-09-0141111910.1186/s13046-022-02497-wGasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activationManuel Gámez-Chiachio0Ángela Molina-Crespo1Carmen Ramos-Nebot2Jeannette Martinez-Val3Lidia Martinez4Katja Gassner5Francisco J. Llobet6Mario Soriano7Alberto Hernandez8Marco Cordani9Cristina Bernadó-Morales10Eva Diaz11Alejandro Rojo-Sebastian12Juan Carlos Triviño13Laura Sanchez14Ruth Rodríguez-Barrueco15Joaquín Arribas16David Llobet-Navás17David Sarrió18Gema Moreno-Bueno19Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM)Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM)Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM)Departamento de Zoología Genética Antropología Física, Universidad Santiago de CompostelaDepartamento de Bioquímica, Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM)Mecanismos Moleculares Y Terapia Experimental en Oncologia-Programa OncobellIdibellMecanismos Moleculares Y Terapia Experimental en Oncologia-Programa OncobellIdibellServicio de Microscopía Electrónica, Centro de Investigación Príncipe Felipe (CIPF)Servicio de Microscopía Óptica Avanzada, Centro de Investigación Príncipe Felipe (CIPF)Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM)Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos IIIFundación MD Anderson InternacionalFundación MD Anderson InternacionalSistemas GenómicosMecanismos Moleculares Y Terapia Experimental en Oncologia-Programa OncobellIdibellDepartamento de Patologia Y Terapèutica Experimental Facultad de Medicina, Unidad de Anatomia Universidad de Barcelona (UB)Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos IIIMecanismos Moleculares Y Terapia Experimental en Oncologia-Programa OncobellIdibellDepartamento de Bioquímica, Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM)Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM)Abstract Background Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Methods Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. Results GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Conclusion Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome.https://doi.org/10.1186/s13046-022-02497-wGasdermin BProtective autophagyAnti-HER2 therapyDrug resistanceHER2 breast cancerGastroesophageal tumors |
| spellingShingle | Manuel Gámez-Chiachio Ángela Molina-Crespo Carmen Ramos-Nebot Jeannette Martinez-Val Lidia Martinez Katja Gassner Francisco J. Llobet Mario Soriano Alberto Hernandez Marco Cordani Cristina Bernadó-Morales Eva Diaz Alejandro Rojo-Sebastian Juan Carlos Triviño Laura Sanchez Ruth Rodríguez-Barrueco Joaquín Arribas David Llobet-Navás David Sarrió Gema Moreno-Bueno Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation Journal of Experimental & Clinical Cancer Research Gasdermin B Protective autophagy Anti-HER2 therapy Drug resistance HER2 breast cancer Gastroesophageal tumors |
| title | Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation |
| title_full | Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation |
| title_fullStr | Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation |
| title_full_unstemmed | Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation |
| title_short | Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation |
| title_sort | gasdermin b over expression modulates her2 targeted therapy resistance by inducing protective autophagy through rab7 activation |
| topic | Gasdermin B Protective autophagy Anti-HER2 therapy Drug resistance HER2 breast cancer Gastroesophageal tumors |
| url | https://doi.org/10.1186/s13046-022-02497-w |
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