Dataset Information

In-depth proteomic analyses reveal unique subtype-specific signatures in small cell lung cancer (part I: cell pellets)

ABSTRACT: Small-cell lung cancer (SCLC) represents about 13–15% of all lung cancers and with a five-year survival rate of less than 7%, it remains one of the most lethal forms of malignant diseases. It has a very aggressive course and is characterized by extensive chromosomal rearrangements, high mutation burden, and almost universal inactivation of the tumor suppressor genes TP53 and RB1. Therefore, the vast majority of SCLC patients are diagnosed with extensive-stage disease when surgery is not feasible and the treatment options are mostly limited to cytotoxic chemotherapy (CHT) and radiation. Importantly, targeted therapies for these patients have so far failed, and the success of immunotherapy in non-SCLC (NSCLC) has not been reflected in SCLC. Although SCLC has been formerly considered as a homogeneous disease with a single morphological type, recent advances in SCLC research have led to the development of subtype-specific classifications primarily based on neuroendocrine (NE) features and unique molecular profiles. Here, we investigate the general cell line characteristics on protein level, the relationship between the RNA-based classification and the protein expression profile, and the distinct biological processes specific for each subtype.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Lung, Cell Culture

DISEASE(S): Lung Small Cell Carcinoma

SUBMITTER: Nicole Woldmar

LAB HEAD: Melinda Rezeli

PROVIDER: PXD029805 | Pride | 2022-10-14

REPOSITORIES: Pride

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Publications

In-depth proteomic analysis reveals unique subtype-specific signatures in human small-cell lung cancer.

Szeitz Beáta B Megyesfalvi Zsolt Z Woldmar Nicole N Valkó Zsuzsanna Z Schwendenwein Anna A Bárány Nándor N Paku Sándor S László Viktória V Kiss Helga H Bugyik Edina E Lang Christian C Szász Attila Marcell AM Pizzatti Luciana L Bogos Krisztina K Hoda Mir Alireza MA Hoetzenecker Konrad K Marko-Varga György G Horvatovich Peter P Döme Balázs B Schelch Karin K Rezeli Melinda M

Clinical and translational medicine 20220901 9

<h4>Background</h4>Small-cell lung cancer (SCLC) molecular subtypes have been primarily characterized based on the expression pattern of the following key transcription regulators: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) and YAP1 (SCLC-Y). Here, we investigated the proteomic landscape of these molecular subsets with the aim to identify novel subtype-specific proteins of diagnostic and therapeutic relevance.<h4>Methods</h4>Pellets and cell media of 26 human SCLC cell lines were subjecte ...[more]

PMID: 36149789

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Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC. The patient-derived cell line models MGH119, MGH121, MGH125, MGH126, MGH131-1, MGH131-2, MGH134 and MGH156 were developed on collagen coated plates in ACL4 medium and transferred to RPMI. MGH157 was developed initially in RPMI. The cell line MGH141 was derived using the feeder system with irradiated fibroblasts (5000 rad) from normal patient tissue. When a tumor cell majority was observed it was passaged off of the feeder layer and later transferred to RPMI medium for experiments. The development of a model was considered complete when it was independent of the feeder system, free of stromal cells, and determined to maintain known patient tumor mutations. MGH119-R was derived in vitro from the treatment naive model, MGH119, through in vitro exposure to gefitinib, escalating from 10nM to a final concentration of 1Î¼M.

Dataset Information

In-depth proteomic analyses reveal unique subtype-specific signatures in small cell lung cancer (part I: cell pellets)

Publications

In-depth proteomic analysis reveals unique subtype-specific signatures in human small-cell lung cancer.

Similar Datasets

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