Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma
Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistan...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1208403/full |
| _version_ | 1797658893864665088 |
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| author | Rodolfo Chavez-Dominguez Rodolfo Chavez-Dominguez Dolores Aguilar-Cazares Mario Perez-Medina Mario Perez-Medina Santiago Avila-Rios Maribel Soto-Nava Alfonso Mendez-Tenorio Lorenzo Islas-Vazquez Jesus J. Benito-Lopez Jesus J. Benito-Lopez Miriam Galicia-Velasco Jose S. Lopez-Gonzalez |
| author_facet | Rodolfo Chavez-Dominguez Rodolfo Chavez-Dominguez Dolores Aguilar-Cazares Mario Perez-Medina Mario Perez-Medina Santiago Avila-Rios Maribel Soto-Nava Alfonso Mendez-Tenorio Lorenzo Islas-Vazquez Jesus J. Benito-Lopez Jesus J. Benito-Lopez Miriam Galicia-Velasco Jose S. Lopez-Gonzalez |
| author_sort | Rodolfo Chavez-Dominguez |
| collection | DOAJ |
| description | Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients. |
| first_indexed | 2024-03-11T18:05:55Z |
| format | Article |
| id | doaj.art-3b7a6ea36b2f4d6ea9f7348e6cdfd619 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-11T18:05:55Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-3b7a6ea36b2f4d6ea9f7348e6cdfd6192023-10-17T06:54:43ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-10-011310.3389/fonc.2023.12084031208403Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinomaRodolfo Chavez-Dominguez0Rodolfo Chavez-Dominguez1Dolores Aguilar-Cazares2Mario Perez-Medina3Mario Perez-Medina4Santiago Avila-Rios5Maribel Soto-Nava6Alfonso Mendez-Tenorio7Lorenzo Islas-Vazquez8Jesus J. Benito-Lopez9Jesus J. Benito-Lopez10Miriam Galicia-Velasco11Jose S. Lopez-Gonzalez12Departamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, MexicoPosgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, MexicoDepartamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, MexicoDepartamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, MexicoEscuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Ciudad de Mexico, MexicoCentro de Investigacion en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Ciudad de Mexico, MexicoCentro de Investigacion en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Ciudad de Mexico, MexicoLaboratorio de Biotecnologia y Bioinformatica Genomica, Departamento de Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Ciudad de Mexico, MexicoDepartamento de Inmunologia y Unidad de Investigacion, Instituto de Oftalmologia “Conde de Valenciana”, Ciudad de Mexico, MexicoDepartamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, MexicoPosgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, MexicoDepartamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, MexicoDepartamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, MexicoResistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.https://www.frontiersin.org/articles/10.3389/fonc.2023.1208403/fulllung cancernon-small cell lung carcinomalung adenocarcinomacisplatinchemotherapy resistanceintrinsic resistance |
| spellingShingle | Rodolfo Chavez-Dominguez Rodolfo Chavez-Dominguez Dolores Aguilar-Cazares Mario Perez-Medina Mario Perez-Medina Santiago Avila-Rios Maribel Soto-Nava Alfonso Mendez-Tenorio Lorenzo Islas-Vazquez Jesus J. Benito-Lopez Jesus J. Benito-Lopez Miriam Galicia-Velasco Jose S. Lopez-Gonzalez Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma Frontiers in Oncology lung cancer non-small cell lung carcinoma lung adenocarcinoma cisplatin chemotherapy resistance intrinsic resistance |
| title | Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma |
| title_full | Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma |
| title_fullStr | Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma |
| title_full_unstemmed | Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma |
| title_short | Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma |
| title_sort | transcriptional signature of early cisplatin drug tolerant persister cells in lung adenocarcinoma |
| topic | lung cancer non-small cell lung carcinoma lung adenocarcinoma cisplatin chemotherapy resistance intrinsic resistance |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1208403/full |
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