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Background: Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma., Methods: Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected., Results: We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043)., Conclusions: Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS -mutant tumors have more rapid progression of the secondary nodules., 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-24-165/coif). N.S.L. received research grants with payments from Intuitive Foundation Centese, consulting fees as data safety monitor for clinical trial with payments from Intuitive Surgical, and honoraria for lecture from MEC MMC; W.L.T. purchased stock in these companies (Eli Lilly and Company, Amgen Inc. Kiniksa Pharmaceuticals) several months ago for reasons unrelated to this manuscript; L.M.B. received Research Grant from Department of Veterans Affairs, Chan Zuckerberg Foundation and NIH, and received speaker bureaus/honoraria from MJH Health Sciences, and from Kazan LLP and Craddick LLP for legal expert consulting, and served on Advisory Board for Genentech, Bristol Meyers Squibb, Astra Zeneca and Ethicon/Johnson& Johnson, and served as Board of Directors from Society of Thoracic Surgeons; J.B.S. received payment of consulting on immunotherapy for lung cancer from Astra Zeneca, and was Chair of Society of Thoracic Surgeons Workforce on General Thoracic Surgery (unpaid). The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics., (© 2024 Wu et al.)

Objective: Robotic thoracic surgery provides another minimally invasive approach in addition to video-assisted thoracoscopic surgery (VATS) that yields less pain and faster recovery compared with open surgery. However, robotic incisions are generally placed more inferiorly, which may increase the risk of intercostal nerve injury that affects the abdominal wall. We hypothesized that a robotic approach causes greater ipsilateral rectus muscle atrophy compared with open and VATS approaches., Methods: The cross-sectional area and density of bilateral rectus abdominis muscles were measured on computed tomography scans in patients who underwent lobectomy in 2018. The differences between the contralateral and ipsilateral muscles were compared between preoperative and 6-month surveillance scans. Changes were compared among the open, VATS, and robotic approaches through a mixed effects model after adjustments of correlation and covariates., Results: Of 99 lobectomies, 25 (25.3%) were open, 56 (56.6%) VATS, and 18 (18.1%) robotic. The difference between the contralateral and ipsilateral rectus muscle cross-sectional area was significantly larger at 6 months after robotic surgery compared with open (31.4% vs 9.5%, P  = .049) and VATS (31.4% vs 14.1%, P  = .021). There were no significant differences in the cross-sectional area between the open and VATS approach., Conclusions: In this retrospective analysis, there was greater ipsilateral rectus muscle atrophy associated with robotic thoracic surgery compared with open or VATS approaches. These findings should be correlated with clinical symptoms and followed to assess for resolution or persistence., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary alveolar epithelial type II (AT2) cells 1 . Here we demonstrate a different scenario: expression of KRAS(G12D) in differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 stem cells that go on to generate indolent tumours. Like human lepidic adenocarcinoma, the tumour cells slowly spread along alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant WNT activation and KRAS(G12D) induction, which accelerates AT2-derived but inhibits AT1-derived adenoma proliferation. Augmentation of ERK activity in KRAS(G12D)-induced AT1 cells increases transformation efficiency, proliferation and progression from lepidic to mixed tumour histology. Overall, we have identified a new cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic KRAS to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer's current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behaviour., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Lung cancer is the leading cause of cancer deaths worldwide 1 . Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis 1-4 , but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type 1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA sequencing and ATAC sequencing of LUAD cells uncovered a p53-induced AT1 differentiation programme during tumour suppression in vivo through direct DNA binding, chromatin remodelling and induction of genes characteristic of AT1 cells. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 cell differentiation in alveolar injury repair. Notably, p53 inactivation results in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signalling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of Trp53 wild-type and Trp53-null mice showed that p53 also directs alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumour suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Both primary lung adenocarcinoma and benign processes can have a ground-glass opacity (GGO) appearance on imaging. This study evaluated the incidence of and risk factors for malignancy in a diverse cohort of patients who underwent resection of a GGO suspicious for lung cancer., Methods: All patients who underwent resection of a pulmonary nodule with a GGO component and suspected to be primary lung cancer at a single institution from 2001-2017 were retrospectively reviewed. Risk factors for malignancy were evaluated using multivariable logistic regression analysis that included nodule size, age, sex, and race as potential predictors., Results: The incidence of pulmonary adenocarcinoma in the 243 patients who met inclusion criteria was 86% (n=208). The most common pathologic findings in 35 patients with a benign pathology was granulomatous inflammation (n=14, 40%). Risk factors for adenocarcinoma in multivariable logistic regression were age [odds ratio (OR) 1.06, P=0.003], GGO size (OR 2.76, P<0.001), female sex (OR 4.47, P=0.002), and Asian race (OR 8.35, P=0.002). In this cohort, adenocarcinoma was found in 100% (44/44) of Asian females, 86% (25/29) of Asian males, 84% (98/117) of non-Asian females, and 77% (41/53) of non-Asian males., Conclusions: The likelihood of adenocarcinoma in lung nodules with a ground-glass component is influenced by sex and race. Asian females with a GGO have a much higher likelihood of having adenocarcinoma than men and non-Asians. This data can be used when deciding whether to pursue nodule resection or surveillance in a patient with a GGO., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-583/coif). NL reports grants from the Intuitive Foundation and Auspex Diagnostics. She serves as an unpaid editorial board member of Journal of Thoracic Disease from September 2021 to August 2023. LB reports grants from the Department of Veterans Affairs, National Institutes of Health, Chan Zuckerberg Institute, consulting fees from Bristol Squibb Myers, Genentech, and Johnson & Johnson, speaker honoraria from International Lung Cancer Congress, and support for attending meeting from national lung cancer roundtable. MFB serves as an unpaid editorial board member of Journal of Thoracic Disease from September 2020 to August 2022. The other authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

Cellular cross-talk in tissue microenvironments is fundamental to normal and pathological biological processes. Global assessment of cell-cell interactions (CCIs) is not yet technically feasible, but computational efforts to reconstruct these interactions have been proposed. Current computational approaches that identify CCI often make the simplifying assumption that pairwise interactions are independent of one another, which can lead to reduced accuracy. We present REMI (REgularized Microenvironment Interactome), a graph-based algorithm that predicts ligand-receptor (LR) interactions by accounting for LR dependencies on high-dimensional, small-sample size datasets. We apply REMI to reconstruct the human lung adenocarcinoma (LUAD) interactome from a bulk flow-sorted RNA sequencing dataset, then leverage single-cell transcriptomics data to increase the cell type resolution and identify LR prognostic signatures among tumor-stroma-immune subpopulations. We experimentally confirmed colocalization of CTGF:LRP6 among malignant cell subtypes as an interaction predicted to be associated with LUAD progression. Our work presents a computational approach to reconstruct interactomes and identify clinically relevant CCIs.