Dataset Information

Pten and p53 Loss in the Mouse Lung Causes Adenocarcinoma and Sarcomatoid Carcinoma.

ABSTRACT: Lung cancer remains the leading cause of cancer deaths worldwide. Among the Non-Small Cell Carcinoma (NSCLC) category, Adenocarcinoma (ADC) represents the most common type, with different reported driver mutations, a bunch of models described and therapeutic options. Meanwhile, Pulmonary Sarcomatoid Carcinoma (PSC) is one of the rarest, with very poor outcomes, scarce availability of patient material, no effective therapies and no models available for preclinical research. Here, we describe that the combined deletion of Pten and Trp53 in the lungs of adult conditional mice leads to the development of both ADC and PSC irrespective of the lung targeted cell type after naphthalene induced airway epithelial regeneration. Although this model shows long latency periods and incomplete penetrance for tumor development, it is the first PSC mouse model reported so far, and sheds light on the relationships between ADC and PSC and their cells of origin. Moreover, human ADC show strong transcriptomic similarities to the mouse PSC, providing a link between both tumor types and the human ADC.

SUBMITTER: Lazaro S

PROVIDER: S-EPMC9367331 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Pten and p53 Loss in the Mouse Lung Causes Adenocarcinoma and Sarcomatoid Carcinoma.

Lázaro Sara S Lorz Corina C Enguita Ana Belén AB Seller Iván I Paramio Jesús M JM Santos Mirentxu M

Cancers 20220728 15

Lung cancer remains the leading cause of cancer deaths worldwide. Among the Non-Small Cell Carcinoma (NSCLC) category, Adenocarcinoma (ADC) represents the most common type, with different reported driver mutations, a bunch of models described and therapeutic options. Meanwhile, Pulmonary Sarcomatoid Carcinoma (PSC) is one of the rarest, with very poor outcomes, scarce availability of patient material, no effective therapies and no models available for preclinical research. Here, we describe that ...[more]

PMID: 35954335

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Project description:BackgroundPhenotypic transition is a common resistance mechanism of targeted therapy. While transformations from lung adenocarcinoma (LUAD) to small-cell lung cancer or squamous-cell carcinoma have been extensively studied, the conversion into sarcomatoid carcinoma (SC) is rarely reported.MethodsGenetic and histological examinations were systematically performed on tumor re-biopsy samples obtained from patients with advanced EGFR-mutant LUAD who progressed on EGFR-tyrosine kinase inhibitors (TKIs). EGFR wild-type patients were also identified who underwent the rare transformation from adenocarcinoma to SC following the ineffectiveness of inhibitors that target distinct driver oncogenes. Furthermore, we also retrospectively collected 42 cases diagnosed with primary pulmonary SC as a comparison cohort to comprehensively characterize the biological events and clinical outcomes of transformed SC.ResultsThe sarcomatoid transformation mediated drug resistance in 2.5 % and 4.8 % of patients after failure on the first/second, and third-generation EGFR-TKIs. Transformation of sarcomatoid carcinoma is characterized by a higher frequency of TP53, RB1, and MET genetic alterations compared to cases lacking histological transformation; the PI3K signaling pathway was also significantly activated. Fifteen individuals were identified with a rare transition from adenocarcinoma to SC, consisting of seven cases with EGFR-activating mutations and eight cases without EGFR mutations. All sarcomatoid-transformed samples not only retained their original driver mutations but also shared specific genetic alterations with primary LUAD. Moreover, transformed sarcomatoid carcinomas mimic the primary SC in terms of immunochemical and molecular features.ConclusionsThe transformation from lung adenocarcinoma to SC is a resistance mechanism wildly applied to inhibitors targeting different driver oncogenes. Immunotherapy plus chemotherapy shows potential to benefit patients with sarcomatoid transformation and warrants further study in larger cohorts.

Dataset Information

Pten and p53 Loss in the Mouse Lung Causes Adenocarcinoma and Sarcomatoid Carcinoma.

Publications

Pten and p53 Loss in the Mouse Lung Causes Adenocarcinoma and Sarcomatoid Carcinoma.

Similar Datasets

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