Notch1 Deficiency Induces Tumor Cell Accumulation Inside the Bronchiolar Lumen and Increases TAZ Expression in an Autochthonous Driven Lung Cancer Mouse Model.

Abrogation of Notch signaling, which is pivotal for lung development and pulmonary epithelial cell fate decisions was shown to be involved in the aggressiveness and the differentiation of lung carcinomas. Additionally, the transcription factors YAP and TAZ which are involved in the Hippo pathway, were recently shown to be tightly linked with Notch signaling and to regulate the cell fate in epidermal stem cells. Thus, we aim to elucidate the effects of conditional Notch1 deficiency on carcinogenesis and TAZ expression in lung cancer.

The benefits of the Papanicolaou Society of Cytopathology System for reporting pancreatobiliary cytology: A 2-year review from a single academic institution.

Objective: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an essential tool in the diagnosis of pancreatic lesions. The aim of this study was to evaluate the diagnostic accuracy of cytology from EUS-FNA, to correlate the results with the corresponding histopathological diagnoses and to analyse the impact of retrospective assignment of the Papanicolaou Society of Cytopathology (PSC) reporting system categories.

Methods: All pancreatic FNA specimens reported at the Royal Free Hospital during a 2-year period were retrospectively collected and assigned to the PSC system categories.

Gallbladder carcinosarcoma masquerading as a hepatic abscess.

Carcinosarcomas of the gallbladder are extremely rare tumors and infrequently reported in the literature. We demonstrate a case of a 64-year-old female who presented with a 2-month history of a right upper quadrant mass, intermittent fevers, and abdominal distension following recent travel to Ghana. A computed tomography (CT) scan of the abdomen and pelvis demonstrated a large hepatic lesion with co-existing gallbladder distension, suggestive of a hepatic abscess.

Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC.

Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in ∼20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a pro-invasive phenotype. Drug-induced inhibition of tumor VEGFR2 interferes with the formation of the EphA2/VEGFR2 heterocomplex, thereby allowing RSK to interact with Serine 897 of EphA2.

MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer.

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a.

EZH2 Is Overexpressed in -like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy.

Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human -deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in -deficient murine mammary tumors.

Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing.

Author Correction: LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells.

The epigenetic writer lysine-specific demethylase 1 (LSD1) is aberrantly upregulated in many cancer types and its overexpression correlates with poor survival and tumor progression. In this study, we analysed LSD1 function in non-small cell lung cancer adenocarcinomas. Expression profiling of 182 cases of lung adenocarcinoma proved a significant correlation of LSD1 overexpression with lung adenocarcinoma progression and metastasis.

Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner.

Unlabelled: KRAS-mutant lung adenocarcinoma is among the most common cancer entities and, in advanced stages, typically displays poor prognosis due to acquired resistance against chemotherapy, which is still largely based on cisplatin-containing combination regimens. Mechanisms of cisplatin resistance have been extensively investigated, and ERCC1 has emerged as a key player due to its central role in the repair of cisplatin-induced DNA lesions. However, clinical data have not unequivocally confirmed ERCC1 status as a predictor of the response to cisplatin treatment.

Implementing amplicon-based next generation sequencing in the diagnosis of small cell lung carcinoma metastases.

Small cell lung carcinoma (SCLC) is the most aggressive entity of lung cancer. Rapid cancer progression and early formation of systemic metastases drive the deadly outcome of SCLC. Recent advances in identifying oncogenes by cancer whole genome sequencing improved the understanding of SCLC carcinogenesis.

NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas.

Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur.

Comprehensive genomic profiles of small cell lung cancer.

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation.

A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells.

The histone code reader SPIN1 controls RET signaling in liposarcoma.

The histone code reader Spindlin1 (SPIN1) has been implicated in tumorigenesis and tumor growth, but the underlying molecular mechanisms remain poorly understood. Here, we show that reducing SPIN1 levels strongly impairs proliferation and increases apoptosis of liposarcoma cells in vitro and in xenograft mouse models. Combining signaling pathway, genome-wide chromatin binding, and transcriptome analyses, we found that SPIN1 directly enhances expression of GDNF, an activator of the RET signaling pathway, in cooperation with the transcription factor MAZ.

PD-L1 expression in small cell neuroendocrine carcinomas.

Small cell lung cancer and extrapulmonary small cell carcinomas are the most aggressive type of neuroendocrine carcinomas. Clinical treatment relies on conventional chemotherapy and radiotherapy; relapses are frequent. The PD-1/PD-L1/PD-L2 pathway is a major target of anti-tumour immunotherapy.

Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.

Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors.

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.

Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes.

A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation.

The linker histone H1 is a key player in chromatin organization, yet our understanding of the regulation of H1 functions by post-translational modifications is very limited. We provide here the first functional characterization of H1 acetylation. We show that H1.

The role of molecular diagnostics in cancer diagnosis and treatment.

The field of molecular diagnostics has improved our understanding of the pathophysiological mechanisms of malignant alteration, especially in lung cancer which remains the leading cause of cancer-related mortality worldwide. The role of the epidermal growth factor receptor (EGFR) and other molecules linked to the EGFR signaling pathway has been extensively studied, and they have become the target of new, specific therapies in lung adenocarcinomas. Similarly, the amplification of the fibroblast growth factor receptor 1 (FGFR1) gene described in squamous cell lung carcinomas has opened new possibilities for molecular targeted therapy.

Late life depression: challenge or curse for the general practitioner (GP). A cohort study.

The aim of this study was to examine specificity of GP's care for elderly depressed patients. Among 17,000 examinees (10 GP-Offices) were extracted 231 patients with diagnosis of depressive episode (F32) and 152 with diagnosis of recurrent depressive disorder (F33) classified according to ICD-10. Older than 65 years were 134 depressed patients.