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Simple Summary: TMEM176B has been reported to play a significant role in the regulation of dendritic cell maturation and other immune functions. Additionally, TMEM176B has been implicated in the development of various cancers, including breast cancer and colorectal cancer, where its expression levels correlate with disease progression and patient outcomes. This study aims to investigate the role of TMEM176B in the development of lung adenocarcinoma (LUAD). Our research indicates that the overexpression of TMEM176B is associated with a poor prognosis in LUAD patients, signifying more aggressive disease and reduced survival rates. Moreover, we have found that TMEM176B overexpression enhances the epithelial-mesenchymal transition (EMT) via the FGFR/JNK signalling pathway. This pathway is integral to cell growth, differentiation, and survival and its dysregulation can contribute to tumour progression and metastasis. These findings suggest that TMEM176B could serve as a potential therapeutic target for LUAD treatment, offering new avenues for developing targeted therapies. Lung cancer, the leading cause of cancer-related incidence and mortality worldwide, is characterised by high invasiveness and poor prognosis. Novel therapeutic targets are required, especially for patients with inoperable metastatic disease requiring systemic therapies to improve patients' welfare. Recently, studies indicated that TMEM176B is a positive regulator in breast and gastric cancers, and it could be a potential target for treatment. In this study, we used single-cell sequencing, proteomics, Co-IP, and in vivo and in vitro experimental models to investigate the role of TMEM176B in lung adenocarcinoma development. Our study indicated that TMEM176B expression was enhanced in lung adenocarcinoma tissues, and it was associated with shorter overall survival (OS). TMEM176B promoted cellular functions, including cell proliferation, invasion, migration and adhesion in vitro and tumour growth in vivo. Moreover, the tube formation ability of endothelial cells was enhanced by treating with the tumour cell-conditioned medium. We have also demonstrated that TMEM176B regulated EMT via the FGFR1/JNK/Vimentin/Snail signalling cascade. Overall, our study suggests TMEM176B could be a potential therapeutic target in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4ΔL12_16) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4ΔL12_16 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4ΔL12_16 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4ΔL12_16 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy. Patients with lung adenocarcinoma (LUAD) patients carrying EGFR mutations are often treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), but sensitivity to the therapy varies. Here, using 3D printed patient derived xenograft models, the authors identify a NOTCH mutation as an indicator of favourable response to EGFR-TKI in LUAD. [ABSTRACT FROM AUTHOR]

Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4 ΔL12_16 ) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4 ΔL12_16 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4 ΔL12_16 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4 ΔL12_16 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4 ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy., (© 2023. The Author(s).)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-617/coif). TH serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2022 to December 2023. AR serves as an unpaid editorial board member of Translational Lung Cancer Research from November 2020 to October 2022. RAR serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2022 to December 2023. MP serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2021 to September 2023. RAR has been a consultant for Amgen, Ipsen Biopharmaceuticals, Novartis, Advanced Accelerator Applications, Curium Pharma, EMD Serono, Astra-Zeneca. He has also received research funding (to institution) from Merck & Co and Aadi Biosciences. He is also on the speaker bureaus for Ipsen Biopharmaceuticals and Astra-Zeneca. Mariano Provencio received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and consulting fees from BMS, Astra Zéneca, MSD, Roche, Takeda and Pfizer. Jay M. Lee reports advisory board/consultant of Astrazeneca, Bristol Myers Squibb, Genentech, Novartis, Roche; research support from Genentech, Novartis; steering committee of Genentech, Novartis; speaker’s bureau of AstraZeneca, Genentech, Roche; stock from Moderna; patents of UCLA. Antonio Passaro received honoraria for consulting, advisory role or lectures from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Jansenn, Merck Sharp & Dohme, Roche Genentech, Novartis, MundiPharma, Daiichi Sankyo, eCancer and Medscape. TC reports speaker fees/honoraria from The Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche, Medscape, and PeerView; travel, food and beverage expenses from Dava Oncology; advisory role/consulting fees from AstraZeneca, Bristol Myers Squibb, EMD Serono, Merck & Co., Genentech, and Arrowhead Pharmaceuticals; and institutional research funding from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim and EMD Serono. The other authors have no conflicts of interest to declare.