Differential development of large-cell neuroendocrine or small-cell lung carcinoma upon inactivation of 4 tumor suppressor genes
Menée sur des modèles murins, cette étude analyse le développement de carcinomes pulmonaires neuroendocrines à petites cellules ou à grandes cellules lors de l'inactivation de 4 gènes suppresseurs de tumeurs
High-grade neuroendocrine tumors (large-cell neuroendocrine cell carcinoma, LCNEC, and small-cell lung carcinoma, SCLC) are recalcitrant cancers for which more effective treatments and follow-up detection systems are urgently needed. Moreover, the relationship between LCNEC and SCLC is largely unknown and a current matter of debate. Human material is scarcely available, making animal models of pivotal importance. Here we report 2 robust models of LCNEC and SCLC remarkably similar to their human counterparts. We show that SCLC can arise from basal cells, which determines the evolution of the high malignant neuroendocrine lung tumor type. Besides, we provide a noninvasive imaging method based on Ga-DOTATOC to monitor changes and assess evaluation of the diseases.High-grade neuroendocrine lung malignancies (large-cell neuroendocrine cell carcinoma, LCNEC, and small-cell lung carcinoma, SCLC) are among the most deadly lung cancer conditions with no optimal clinical management. The biological relationships between SCLC and LCNEC are still largely unknown and a current matter of debate as growing molecular data reveal high heterogeneity with potential therapeutic consequences. Here we describe murine models of high-grade neuroendocrine lung carcinomas generated by the loss of 4 tumor suppressors. In an Rbl1-null background, deletion of Rb1, Pten, and Trp53 floxed alleles after Ad-CMVcre infection in a wide variety of lung epithelial cells produces LCNEC. Meanwhile, inactivation of these genes using Ad-K5cre in basal cells leads to the development of SCLC, thus differentially influencing the lung cancer type developed. So far, a defined model of LCNEC has not been reported. Molecular and transcriptomic analyses of both models revealed strong similarities to their human counterparts. In addition, a 68Ga-DOTATOC–based molecular-imaging method provides a tool for detection and monitoring the progression of the cancer. These data offer insight into the biology of SCLC and LCNEC, providing a useful framework for development of compounds and preclinical investigations in accurate immunocompetent models.