A role for club cells in smoking-associated lung adenocarcinoma

The cellular origin of lung adenocarcinoma remains a focus of intense research efforts. The marked cellular heterogeneity and plasticity of the lungs, as well as the vast variety of molecular subtypes of lung adenocarcinomas perplex the field and account for the extensive variability of experimental results. While most experts would agree on the cellular origins of other types of thoracic tumours, great controversy exists on the tumour-initiating cells of lung adenocarcinoma, since this histologic subtype of lung cancer arises in the distal pulmonary regions where airways and alveoli converge, occurs in smokers as well as nonsmokers, is likely caused by various environmental agents, and is marked by vast molecular and pathologic heterogeneity. Alveolar type II, club, and their variant cells have all been implicated in lung adenocarcinoma progeny and the lineage hierarchies in the distal lung remain disputed. Here we review the relevant literature in this rapidly expanding field, including results from mouse models and human studies. In addition, we present a case for club cells as cells of origin of lung adenocarcinomas that arise in smokers.

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Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2

Nature Communications ◽

10.1038/ncomms14922 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 29

Author(s):

Haikuo Zhang ◽

Christine Fillmore Brainson ◽

Shohei Koyama ◽

Amanda J. Redig ◽

Ting Chen ◽

...

Keyword(s):

Poor Prognosis ◽

Human Lung ◽

Polycomb Repressive Complex ◽

Isolated Populations ◽

Lung Tumours ◽

Polycomb Repressive Complex 2 ◽

Cells Of Origin ◽

Club Cells ◽

Lung Adenocarcinomas ◽

Shed Light

Abstract Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.

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The tyrosine kinase TEK is differentially expressed in non-small cell lung adenocarcinomas.

10.31219/osf.io/sk8r4 ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

United States ◽

Tyrosine Kinase ◽

Lung Adenocarcinoma ◽

Microarray Data ◽

The United States ◽

Small Cell ◽

Small Cell Lung ◽

Significant Differential Expression ◽

Lung Cancers ◽

Lung Adenocarcinomas

Non-small cell lung adenocarcinoma (NSCLC) is a leading cause of death in the United States and worldwide (1, 2). We mined published microarray data (3, 4, 5) to discover genes associated with NSCLC. We identified significant differential expression of the tyrosine kinase TEK in tumors from patients with NSCLC. TEK may be of relevance to the initiation, progression or maintenance of non-small cell lung cancers.

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ATRT-13. DIFFERENT CELLS OF ORIGIN PAVE THE WAY FOR MOLECULAR HETEROGENEITY IN RHABDOID TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.012 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii278-iii278

Author(s):

Monika Graf ◽

Marta Interlandi ◽

Natalia Moreno ◽

Dörthe Holdhof ◽

Viktoria Melcher ◽

...

Keyword(s):

Single Cell ◽

Expression Patterns ◽

Time Frame ◽

Precursor Cells ◽

Genetically Engineered ◽

Molecular Heterogeneity ◽

Loss Of Function ◽

Cellular Origin ◽

Cells Of Origin ◽

Rhabdoid Tumors

Abstract Rhabdoid tumors (RT) are rare but highly aggressive pediatric neoplasms. These tumors carry homozygous loss-of-function alterations of SMARCB1 in almost all cases with an otherwise low mutational load. RT arise at different intracranial (ATRT) as well as extracranial (MRT) anatomical sites. Three main molecular subgroups (ATRT-SHH, ATRT-TYR, ATRT-MYC) have been characterized for ATRT which are epigenetically and clinically diverse, while MRT show remarkable similarities with ATRT-MYC distinct from ATRT-SHH and ATRT-TYR. Even though there are hypotheses about various cells of origin among RT subgroups, precursor cells of RT have not yet been identified. Previous studies on the temporal control of SMARCB1 knockout in genetically engineered mouse models have unveiled a tight vulnerable time frame during embryogenesis with regard to the susceptibility of precursor cells to result in RT. In this study, we employed single-cell RNA sequencing to describe the intra- and intertumoral heterogeneity of murine ATRT-SHH and -MYC as well as extracranial MYC tumor cells. We defined subgroup-specific tumor markers for all RT classes but also observed a notable overlap of gene expression patterns in all MYC subgroups. By comparing these single-cell transcriptomes with available single-cell maps of early embryogenesis, we gained first insights into the cellular origin of RT. Finally, unsupervised clustering of published human RT methylation data and healthy control tissues confirmed the existence of different cells of origin for intracranial SHH tumors and MYC tumors independent of their anatomical localizations.

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Identification of lung adenocarcinoma mutation status based on histologic subtype: Retrospective analysis of 269 patients

Thoracic Cancer ◽

10.1111/1759-7714.12265 ◽

2015 ◽

Vol 7 (1) ◽

pp. 17-23 ◽

Cited By ~ 5

Author(s):

Fangliang Lu ◽

Shaolei Li ◽

Bin Dong ◽

Shanyuan Zhang ◽

Chao Lv ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Retrospective Analysis ◽

Histologic Subtype ◽

Mutation Status

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Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

10.1101/2020.04.13.036921 ◽

2020 ◽

Author(s):

Giorgia Foggetti ◽

Chuan Li ◽

Hongchen Cai ◽

Jessica A. Hellyer ◽

Wen-Yang Lin ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Growth ◽

Lung Adenocarcinoma ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Genetic Alterations ◽

Putative Tumor Suppressor ◽

Lung Adenocarcinomas ◽

Gene Alterations

AbstractCancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which are the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumor growth. These results are consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduces the sensitivity of EGFR-driven Trp53-deficient tumors to the EGFR inhibitor osimertinib. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.

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miR-1293 acts as a tumor promotor in lung adenocarcinoma via targeting phosphoglucomutase 5

PeerJ ◽

10.7717/peerj.12140 ◽

2021 ◽

Vol 9 ◽

pp. e12140

Author(s):

Bing Chen ◽

Shiya Zheng ◽

Feng Jiang

Keyword(s):

Lung Adenocarcinoma ◽

Cell Lines ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Ki 67 ◽

Histologic Subtype ◽

Tumor Promotor ◽

Common Histologic Subtype ◽

The Relationship

Background Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Studies have found that miR-1293 is related to the survival of LUAD patients. Unfortunately, its role in LUAD remains not fully clarified. Methods miR-1293 expression and its association with LUAD patients’ clinical characteristics were analyzed in TCGA database. Also, miR-1293 expression was detected in LUAD cell lines. Cell viability, migration, invasion and expression of MMP2 and MMP9 were measured in LUAD cells following transfection with miR-1293 mimic or antagomir. Phosphoglucomutase (PGM) 5 was identified to be negatively related to miR-1293 in LUAD patients in TCGA database, and their association was predicated by Targetscan software. Hence, we further verified the relationship between miR-1293 and PGM5. Additionally, the effect and mechanism of miR-1293 were validated in a xenograft mouse model. Results We found miR-1293 expression was elevated, but PGM5 was decreased, in LUAD patients and cell lines. Higher miR-1293 expression was positively related to LUAD patients’ pathologic stage and poor overall survival. miR-1293 mimic significantly promoted, whereas miR-1293 antagomir suppressed the viability, migration, invasion, and expression of MMP2 and MMP9 in LUAD cells. PGM5 was a target of miR-1293. Overexpression of PGM5 abrogated the effects of miR-1293 on the malignant phenotypes of LUAD cells. Administration of miR-1293 antagomir reduced tumor volume and staining of Ki-67 and MMP9, but elevated PGM5 expression in vivo. Conclusions miR-1293 promoted the proliferation, migration and invasion of LUAD cells via targeting PGM5, which indicated that miR-1293 might serve as a potential therapeutic target for LUAD patients.

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Histopathologic Features From Preoperative Biopsies to Predict Spread Through Air Spaces in Early Stage Lung Adenocarcinoma: A Retrospective Study

10.21203/rs.3.rs-854891/v1 ◽

2021 ◽

Author(s):

Lanqing Cao ◽

Meng Jia ◽

Ping-Li Sun ◽

Hongwen Gao

Keyword(s):

Lung Adenocarcinoma ◽

Early Stage ◽

Histologic Subtype ◽

Necrotic Tumor ◽

N Stage ◽

Grade 3 ◽

Study Participants ◽

Surgical Extent ◽

Histopathologic Features ◽

Spread Through Air Spaces

Abstract Background: Although spread through air spaces (STAS) is a robust biomarker in surgically resected lung cancer, its application to biopsies is challenging. Moreover, limited resection is not an effective treatment for STAS-positive lung adenocarcinoma. This study aimed to identify histologic features from preoperative percutaneous transthoracic needle biopsies (PTNBs) to predict STAS status in the subsequently resected specimens, and thus help in selecting the surgical extent.Methods: Between January 2014 and December 2015, 111 PTNB specimens and subsequent resection specimens from consecutive lung adenocarcinoma patients were retrospectively examined. Histopathologic features of PTNB specimens and presence of STAS in subsequent resection specimens were evaluated and correlations between them were analyzed statistically.Results: The study participants had a mean age of 59 years (range, 35–81) and included 50 men and 61 women. Thirty-six patients were positive for STAS whereas 75 were negative. The micropapillary/solid histologic subtypes of lung adenocarcinoma (26 of 39; 66.7%; P < 0.001), necrotic/tumor debris (31 of 42; 73.8%; P < 0.001), intratumoral budding (ITB) (20 of 33; 60.6%; P < 0.001), desmoplasia (35 of 41; 85.4%; P < 0.001), and grade 3 nuclei (12 of 14; 85.7%; P < 0.001) were more common in STAS-positive tumors. Micropapillary/solid histologic subtype (OR, 1.35; 95% CI: 1.06, 1.67), ITB (OR, 1.64; 95% CI: 1.09, 2.83), desmoplasia (OR, 1.83; 95% CI: 1.36, 3.12), and N stage (N1 stage: OR, 1.37; 95% CI: 1.19, 1.87) (N2 stage: OR, 1.29; 95% CI: 1.07, 1.73) were independent predictors of STAS. Conclusions: Micropapillary/solid histologic subtype, ITB, and desmoplasia in preoperative PTNB specimens were independently associated with STAS in the subsequent resection specimens. Therefore, these can predict STAS and may help to optimize therapeutic planning.

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Aberrant Fucosylation of Saliva Glycoprotein Defining Lung Adenocarcinomas Malignancy

10.1101/2021.12.16.472888 ◽

2021 ◽

Author(s):

Shuang Yang ◽

Ziyuan Gao ◽

Zhen Wu ◽

Ying Han ◽

Xumin Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Early Diagnosis ◽

Lung Adenocarcinoma ◽

Tumor Progression ◽

Cancer Patients ◽

Solid Phase ◽

Clinical Specimens ◽

Aberrant Glycosylation ◽

Lung Adenocarcinomas ◽

Core Fucosylation

Aberrant glycosylation is a hallmark of cancer found during tumorigenesis and tumor progression. Lung cancer induced by oncogene mutations has been detected in the patient's saliva, and saliva glycosylation has been altered. Saliva contains highly glycosylated glycoproteins, the characteristics of which may be related to various diseases. Therefore, elucidating cancer-specific glycosylation in the saliva of healthy, non-cancer, and cancer patients can reveal whether tumor glycosylation has unique characteristics for early diagnosis. In this work, we used a solid-phase chemoenzymatic method to study the glycosylation of saliva glycoproteins in clinical specimens. The results showed that the alpha1,6-core fucosylation of glycoproteins in cancer patients was significant increased. The fucosylation of alpha1,2 or alpha1,3 is also increased in cancer patients. We further analyzed the expression of fucosyltransferases responsible for alpha1,2, alpha1,3, alpha1,6 fucosylation. The fucosylation of the saliva of cancer patients is drastically different from that of non-cancer or health controls. These results indicate that the glycoform of saliva fucosylation distinguishes lung cancer from other diseases, and this feature has the potential to diagnose lung adenocarcinoma.

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Clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20588 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20588-e20588

Author(s):

Linping Gu ◽

Bei Zhang ◽

Ding Zhang ◽

Hong Jian

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

De Novo ◽

Egfr Mutations ◽

Genomic Profiling ◽

Small Cell Lung ◽

Genetic Characteristics ◽

Egfr Mutant ◽

Lung Adenocarcinomas ◽

Egfr T790m

e20588 Background: Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the resistance mechanism of EGFR tyrosine kinase inhibitors. However, the clinical course of transformed SCLC and the difference of genomic profiling between de novo SCLC patients and transformed SCLC patients are still poorly characterized. Methods: Patients from our hospital diagnosed with SCLC were enrolled retrospectively in this study, including de novo SCLC patients and SCLC patients transformed from EGFR-mutant lung adenocarcinomas. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples by next generation sequencing (NGS). In statistical analysis, fisher ‘exact test was used. All tests were bilateral, with P<0.05 indicating significant statistical difference. Results: In total, 16 patients with SCLC transformed from EGFR-mutant lung adenocarcinomas and 230 de novo SCLC patients were included in our study. Transformed SCLC patients were more in younger (p=0.007), female (p<0.001) and non-smokers (p<0.001) than de novo SCLC patients. In transformed SCLC patients, 12 patients (75%) occurred SCLC transformation within 2 years after the lung adenocarcinomas diagnosis. Median transformation time was 20 months. During the treatment of adenocarcinomas, the overall response rate (ORR) was 75% and the median progression-free survival was 12 months. After the initiation of SCLC therapy, the ORR of 1st line chemotherapy was 40%. For the genomic profiling, EGFR mutations, including exon 19 deletion (56%), L858R (38%), and others (6%), were detected. 11 patients with acquired resistance were received EGFR T790M test, 82% of patients had acquired EGFR T790M mutation. 11 patients after transformation to SCLC had NGS test, 100% maintained their founder EGFR mutation, and other recurrent mutations included TP53, RB1 and EGFR amplification. Compared with the genetic alterations in de novo SCLC patients, TP53 mutations were significantly decreased (p=0.006) while EGFR mutations were significantly elevated (p<0.001) in transformed SCLC patients. However, no significant difference on RB1, ALK and ROS1 mutations were observed. Interestingly, a 60-year-old woman in our transformed SCLC cohort harbored EGFR 19 del mutant at allele frequency of 50.39%，she received osimertinib plus epirubicin/cyclophosphamide as 1st line treatment and reached partial response, with survival of 4 years to date. Conclusions: We demonstrated the clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC and found one patient still benefited from EGFR-TKI. Our study suggested that SCLC patients with EGFR mutation who transformed from lung adenocarcinoma may be potential benefit population using EGFR inhibitors.

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395O Potential predictive value for adjuvant PD-1 blockade based on histologic subtype in resected lung adenocarcinoma

Annals of Oncology ◽

10.1093/annonc/mdw588.001 ◽

2016 ◽

Vol 27 (suppl_9) ◽

Author(s):

Z-Y. Dong ◽

W-Z. Zhong ◽

S-Y. Liu ◽

Z. Xie ◽

S-P. Wu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Predictive Value ◽

Histologic Subtype

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