Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells
Background Epithelial to mesenchymal transition (EMT) endows cancer cells with pro-metastatic properties, which appear most effective when cells enter an intermediate hybrid (H) state, characterized by integrated mesenchymal (M) and epithelial (E) traits. The reasons for this advantage are poorly kn...
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| Language: | English |
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BMJ Publishing Group
2024-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/3/e007895.full |
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| author | Ugo Pastorino Massimo Milione Paola Orecchia Massimo Moro Gabriella Sozzi Monica Parodi Giovanni Centonze Fabio Murianni Francesca Andriani Ilaria Roato Cecilia Gardelli Melissa Balsamo Giulia Taiè Andrea Petretto Chiara Lavarello Luca Roz Massimo Vitale Giulia Bertolini |
| author_facet | Ugo Pastorino Massimo Milione Paola Orecchia Massimo Moro Gabriella Sozzi Monica Parodi Giovanni Centonze Fabio Murianni Francesca Andriani Ilaria Roato Cecilia Gardelli Melissa Balsamo Giulia Taiè Andrea Petretto Chiara Lavarello Luca Roz Massimo Vitale Giulia Bertolini |
| author_sort | Ugo Pastorino |
| collection | DOAJ |
| description | Background Epithelial to mesenchymal transition (EMT) endows cancer cells with pro-metastatic properties, which appear most effective when cells enter an intermediate hybrid (H) state, characterized by integrated mesenchymal (M) and epithelial (E) traits. The reasons for this advantage are poorly known and, especially, it is totally unexplored whether the interplay between H-cells and NK cells could have a role. Here we characterize the pro-metastatic mechanics of non-small cell lung cancer (NSCLC) H-cells and their subset of cancer-initiating cells (CICs), dissecting crucial interactions with NK cells.Methods Human lung cancer cell lines and sublines representative of E, M, or H states, assessed by proteomics, were analyzed in vivo for their tumor-forming and disseminating capabilities. Interactions with NK cells were investigated in vitro using migration assays, cytotoxic degranulation assays, and evaluation of CD133+ CICs modulation after coculture, and validated in vivo through NK cell neutralization assays. Correlation between EMT status, NK cell infiltration, and survival data, was evaluated in a cohort of surgically resected NSCLC cases (n=79).Results We demonstrated that H-cells, have limited dissemination capability but show the highest potential to initiate metastases in vivo. This property was related to their ability to escape NK cell surveillance. Mechanistically, H-cells expressed low levels of NK-attracting chemokines (CXCL1 and CXCL8), generating poorly infiltrated metastases. Accordingly, proteomics and GO enrichment analysis of E, H, M cell lines showed that the related secretory processes could change during EMT.Furthermore, H-CICs uniquely expressed high levels of the inhibitory ligand B7-H3, which protected H-CIC from NK cell-mediated clearance. In vivo neutralization assays confirmed that, indeed, the pro-metastatic properties of H-cells are poorly controlled by NK cells.Finally, the analysis of patients revealed that detection of hybrid phenotypes associated with low NK infiltration in NSCLC clinical specimens could identify a subset of patients with poor prognosis.Conclusions Our study demonstrates that H-cells play a central role in the metastatic spread in NSCLC. Such pro-metastatic advantage of H-cells is supported by their altered interaction with NK cells and by the critical role of B7-H3 in preserving their H-CIC component, indicating B7-H3 as a potential target in combined NK-based therapies. |
| format | Article |
| id | doaj-art-f72425c485344776a7a4043b68dafea4 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f72425c485344776a7a4043b68dafea42024-12-18T03:30:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-03-0112310.1136/jitc-2023-007895Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cellsUgo Pastorino0Massimo Milione1Paola Orecchia2Massimo Moro3Gabriella Sozzi4Monica Parodi5Giovanni Centonze6Fabio Murianni7Francesca Andriani8Ilaria Roato9Cecilia Gardelli10Melissa Balsamo11Giulia Taiè12Andrea Petretto13Chiara Lavarello 14Luca Roz15Massimo Vitale16Giulia Bertolini17Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyPathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyImmunology Operative Unit, IRCCS Ospedale Policlinico San Martino, Genova, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyImmunology Operative Unit, IRCCS Ospedale Policlinico San Martino, Genova, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyC.I.R Dental School, Department of Surgical Sciences, University of Turin, Torino, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyCore Facilities, Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, Genova, ItalyCore Facilities, Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, Genova, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyImmunology Operative Unit, IRCCS Ospedale Policlinico San Martino, Genova, ItalyUnit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyBackground Epithelial to mesenchymal transition (EMT) endows cancer cells with pro-metastatic properties, which appear most effective when cells enter an intermediate hybrid (H) state, characterized by integrated mesenchymal (M) and epithelial (E) traits. The reasons for this advantage are poorly known and, especially, it is totally unexplored whether the interplay between H-cells and NK cells could have a role. Here we characterize the pro-metastatic mechanics of non-small cell lung cancer (NSCLC) H-cells and their subset of cancer-initiating cells (CICs), dissecting crucial interactions with NK cells.Methods Human lung cancer cell lines and sublines representative of E, M, or H states, assessed by proteomics, were analyzed in vivo for their tumor-forming and disseminating capabilities. Interactions with NK cells were investigated in vitro using migration assays, cytotoxic degranulation assays, and evaluation of CD133+ CICs modulation after coculture, and validated in vivo through NK cell neutralization assays. Correlation between EMT status, NK cell infiltration, and survival data, was evaluated in a cohort of surgically resected NSCLC cases (n=79).Results We demonstrated that H-cells, have limited dissemination capability but show the highest potential to initiate metastases in vivo. This property was related to their ability to escape NK cell surveillance. Mechanistically, H-cells expressed low levels of NK-attracting chemokines (CXCL1 and CXCL8), generating poorly infiltrated metastases. Accordingly, proteomics and GO enrichment analysis of E, H, M cell lines showed that the related secretory processes could change during EMT.Furthermore, H-CICs uniquely expressed high levels of the inhibitory ligand B7-H3, which protected H-CIC from NK cell-mediated clearance. In vivo neutralization assays confirmed that, indeed, the pro-metastatic properties of H-cells are poorly controlled by NK cells.Finally, the analysis of patients revealed that detection of hybrid phenotypes associated with low NK infiltration in NSCLC clinical specimens could identify a subset of patients with poor prognosis.Conclusions Our study demonstrates that H-cells play a central role in the metastatic spread in NSCLC. Such pro-metastatic advantage of H-cells is supported by their altered interaction with NK cells and by the critical role of B7-H3 in preserving their H-CIC component, indicating B7-H3 as a potential target in combined NK-based therapies.https://jitc.bmj.com/content/12/3/e007895.full |
| spellingShingle | Ugo Pastorino Massimo Milione Paola Orecchia Massimo Moro Gabriella Sozzi Monica Parodi Giovanni Centonze Fabio Murianni Francesca Andriani Ilaria Roato Cecilia Gardelli Melissa Balsamo Giulia Taiè Andrea Petretto Chiara Lavarello Luca Roz Massimo Vitale Giulia Bertolini Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells Journal for ImmunoTherapy of Cancer |
| title | Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells |
| title_full | Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells |
| title_fullStr | Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells |
| title_full_unstemmed | Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells |
| title_short | Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells |
| title_sort | hybrid epithelial mesenchymal status of lung cancer dictates metastatic success through differential interaction with nk cells |
| url | https://jitc.bmj.com/content/12/3/e007895.full |
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