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Hybrid Epithelial-Mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells

ABSTRACT: 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 sub-lines representative of E, M, or H states, assessed by proteomics, were analysed 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 co-culture, 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 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 B7H3 in preserving their H-CIC component, indicating B7H3 as a potential target in combined NK-based therapies.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Cell Culture

SUBMITTER: Martina Bartolucci

LAB HEAD: Andrea Petretto

PROVIDER: PXD044297 | Pride | 2024-05-21

REPOSITORIES: Pride

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Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells.

Parodi Monica M Centonze Giovanni G Murianni Fabio F Orecchia Paola P Andriani Francesca F Roato Ilaria I Gardelli Cecilia C Balsamo Melissa M Moro Massimo M Taiè Giulia G Pastorino Ugo U Petretto Andrea A Lavarello Chiara C Milione Massimo M Sozzi Gabriella G Roz Luca L Vitale Massimo M Bertolini Giulia G

Journal for immunotherapy of cancer 20240307 3

<h4>Background</h4>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 can ...[more]

PMID: 38458638

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Project description:Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC. A 76-gene EMT signature was derived in 54 DNA-fingerprinted NSCLC cell lines and tested in an independent set of cell lines and in NSCLC patients from the BATTLE clinical trial. The signature classified cell lines as epithelial or mesenchymal independent of the microarray platform and correlated strongly with E-cadherin protein levels, as measured by reverse phase protein array. Higher protein expression of Rab25 (in epithelial lines) and Axl (in mesenchymal lines), two signature genes associated with in EMT in other cancer types, was also confirmed. Mesenchymal cell lines demonstrated significantly greater resistance to EGFR inhibition, independent of EGFR mutation status and were more resistant to drugs targeting the PI3K/Akt pathway. We observed no association between EMT and response to cytotoxic chemotherapies, including cisplatin, pemetrexed, and docetaxel monotherapy and/or doublets (p-values ≥0.2). In NSCLC patients, the EMT signature predicted 8-week disease control in the erlotinib arm, but not in other treatment arms. In conclusion, we have developed a robust EMT signature that predicts resistance to EGFR inhibitors and PI3K/Akt pathway inhibitors. Gene expression profiles were measured in 131 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EMT gene expression signature trained in cell lines and independant of the microarray platform.

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