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Doublecortin (DCX)‐positive neural progenitor‐like cells are purported components of the cancer microenvironment. The number of DCX‐positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX‐positive cells, which are found in all major histological subtypes of lung cancer, are cancer‐associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine‐synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues. [ABSTRACT FROM AUTHOR]

Introduction: The percentage of low attenuation area (%LAA) on computed tomography (CT) is useful for evaluating lung emphysema, and higher %LAA was observed in patients with chronic lung allograft dysfunction (CLAD). This study investigated the relationship between the %LAA and the development of CLAD after bilateral lung transplantation (LT). Methods: We conducted a single‐center retrospective study of 75 recipients who underwent bilateral LT; the recipients were divided into a CLAD group (n = 30) and a non‐CLAD group (n = 45). The %LAA was calculated using CT and compared between the two groups from 4 years before to 4 years after the diagnosis of CLAD. The relationships between the %LAA and the percent baseline values of the pulmonary function test parameters were also calculated. Results: The %LAA was significantly higher in the CLAD group than in the non‐CLAD group from 2 years before to 2 years after the diagnosis of CLAD (P <.05). In particular, patients with bronchiolitis obliterans syndrome (BOS) exhibited significant differences even from 4 years before to 4 years after diagnosis (P <.05). Significant negative correlations between the %LAA and the percent baseline values of the forced expiratory volume in 1 s (r = −.36, P =.0031), the forced vital capacity (r = −.27, P =.027), and the total lung capacity (r = −.40, P <.001) were seen at the time of CLAD diagnosis. Conclusion: The %LAA on CT was associated with the development of CLAD and appears to have the potential to predict CLAD, especially BOS, after bilateral LT. [ABSTRACT FROM AUTHOR]

Objectives: S100A8/A9 is a damage‐associated molecule that augments systemic inflammation. However, its role in the acute phase after lung transplantation (LTx) remains elusive. This study aimed to determine S100A8/A9 levels after lung transplantation (LTx) and evaluate their impact on overall survival (OS) and chronic lung allograft dysfunction (CLAD)‐free survival. Methods: Sixty patients were enrolled in this study, and their plasma S100A8/A9 levels were measured on days 0, 1, 2, and 3 after LTx. The association of S100A8/A9 levels with OS and CLAD‐free survival was assessed using univariate and multivariate Cox regression analyses. Results: S100A8/A9 levels were elevated in a time‐dependent manner until 3 days after LTx. Ischemic time was significantly longer in the high S100A8/9 group than in the low S100A8/A9 group (p =.017). Patients with high S100A8/A9 levels (> 2844 ng/mL) had worse prognosis (p =.031) and shorter CLAD‐free survival (p =.045) in the Kaplan–Meier survival analysis than those with low levels. Furthermore, multivariate Cox regression analysis showed that high S100A8/A9 levels were a determinant of poor OS (hazard ratio [HR]: 3.7; 95% confidence interval [CI]: 1.2–12; p =.028) and poor CLAD‐free survival (HR: 4.1; 95% CI: 1.1–15; p =.03). In patients with a low primary graft dysfunction grade (0–2), a high level of S100A8/A9 was also a poor prognostic factor. Conclusions: Our study provided novel insights into the role of S100A8/A9 as a prognostic biomarker and a potential therapeutic target for LTx. [ABSTRACT FROM AUTHOR]

Introduction: Living‐donor lobar lung transplantation is an alternative procedure to deceased donation lung transplantation. It involves graft donation from healthy donors; however, only a few reports have discussed its long‐term prognosis in living lung donors and their associated health‐related quality of life. This study aimed to examine living lung donors' health‐related quality of life. Methods: In our cross‐sectional survey of living lung donors, we assessed health‐related quality of life‐based on three key aspects (physical, mental, and social health) using the 36‐Item Short Form Health Survey. We also evaluated chronic postoperative pain and postoperative breathlessness using the numeric rating scale and the modified Medical Research Council Dyspnea scale, respectively. Results: We obtained consent from 117 of 174 living lung donors. The average scores of the living lung donors on the 36‐Item Short Form Health Survey were higher than the national average. However, some donors had poorer physical, mental, and social health, with lower summary scores than the national averages. Low mental component summary predictors included donor age (<40 years; odds ratio = 10.2; p <.001) and recipient age (<18 years; odds ratio = 2.73; p <.032). Low role‐social component summary predictors included high lung allocation score (≥50; odds ratio = 3.94, p <.002) and recipient death (odds ratio = 3.64; p =.005). There were no predictors for a physical component summary. Additionally, many donors did not complain of pain or dyspnea. Conclusions: Living lung donors maintained an acceptable long‐term health‐related quality of life after surgery. Potential donors should be informed of relevant risk factors, and high‐risk donors should receive appropriate support. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non–small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR‐mutant NSCLC cell lines, two KRAS‐mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial‐mesenchymal transition (EMT), and acquisition of resistance to molecular‐targeted therapy, including EGFR‐mutant NSCLC cells to osimertinib and of KRAS‐mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL‐6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF‐induced phospho‐STAT3 upregulation. Tranilast also inhibited CAF‐induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular‐targeted therapy reversed the CAF‐mediated resistance of the NSCLC cells to the molecular‐targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular‐targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer‐CAF interaction. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2‐hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2‐hiPSCs, which expressed NKX2‐1/TTF‐1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2‐like cells. HLOs that overexpressed HER2 transformed to tumor‐like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2‐hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue‐like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC‐derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression. What's new? Activation of human epidermal growth factor receptor 2 (HER2) likely contributes to the development of precancerous lesions that ultimately give rise to lung adenocarcinoma (LUAD). The mechanism driving HER2 activation in these tumors, however, remains uncertain. Here, HER2 overexpression in human pluripotent stem cell‐derived lung organoids (HLOs) induced the formation of tumor‐like structures, similar to those observed in adenomatous hyperplasia, and transformed the normal lung tissue‐like state of the HLO transcriptome to a state resembling clinical LUAD with HER2 amplification. This novel model for visualization of pre‐malignant transformation could greatly facilitate investigations into the molecular basis of tumor initiation. [ABSTRACT FROM AUTHOR]

Molecular‐targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan‐HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2‐positive breast cancer. However, acquired resistance of various cancers to molecular‐targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib‐resistant cell lines from HER2‐amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1‐amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome. [ABSTRACT FROM AUTHOR]

In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer‐related oncogenes using next‐generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation. For patients with multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). In this research, we carried out targeted sequencing of 20 lung cancer‐related genes using next‐generation sequencing (NGS) for MLC patients and compared the histopathological diagnosis and the mutational diagnosis. Our results suggest that multiplex mutational analysis of MLC could be a useful complementary tool for distinguishing between MP and IM. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 ( HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer ( NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor ( EGFR)- HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775ins YVMA, G776 VC, G776 LC, P780ins GSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. [ABSTRACT FROM AUTHOR]

Afatinib is an irreversible epidermal growth factor receptor ( EGFR)-tyrosine kinase inhibitor ( TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR- TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827- ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827- ACR displayed epithelial-to-mesenchymal transition ( EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR- TKIs. This finding may provide clues to overcoming resistance to EGFR- TKIs. [ABSTRACT FROM AUTHOR]