Differential development of large-cell neuroendocrine or small-cell lung carcinoma upon inactivation of 4 tumor suppressor genes

Abstract

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 highgrade 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 68 Ga-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.LCNEC | SCLC | cell of origin | tumor suppressor

Cells of origin of lung cancers: lessons from mouse studies

“…In this model, the efficiency of transformation into SCLC as well as tumor latency matched that of mice injected with Ad5-CGRP-Cre, raising the possibility that a subpopulation of K14 + cells in lung is receptive to neuroendocrine transformation. Accordingly, deletion of Rb1 and Trp53 along with Pten and Rbl1 (p107) with Ad5-K5-Cre, which targets cells similar to K14-expressing cells, also led to the development of SCLC, supporting the idea that basal cells can serve as a cell of origin for SCLC in the context of a different set of driver lesions (Lázaro et al 2019).…”

“…While the neuroendocrine phenotype and common occurrence of RB1 loss in large cell neuroendocrine carcinoma of the lung (LCNEC) have suggested potential ties between this cancer type and SCLC (George et al 2018), a robust mouse model of LCNEC development has not yet been developed. Recently, however, combining Pten deletion alongside Trp53/Rb1/Rbl1 loss, which normally leads to SCLC development (Ng et al 2020), has been shown to generate LCNEC in mouse models (Lázaro et al 2019). Targeting the quadruple knockout to all cell lineages with Ad5-CMV-Cre resulted in a majority of tumors being LCNEC while targeting basal cells with Ad-K5-Cre resulted mostly in SCLC.…”

Development and long-term evaluation of a new 68Ge/68Ga generator based on nano-SnO2 for PET imaging

“…We used lung cancer mouse models generated in the laboratory to determine the suitability of the [ 68 Ga]Ga-DOTA-TOC obtained for detection of tumors in vivo by PET imaging. We have used a high-grade neuroendocrine lung cancer animal model rendering Large-Cell Neuroendocrine Carcinoma (LCNEC) 33,34 . LCNEC is an aggressive, poorly differentiated pulmonary neuroendocrine tumor which expresses a high density of surface somatostatin receptors (SSTR).…”

“…It is widely used in clinical routines for PET imaging of neuroendocrine tumors 37 . The procedure used to label, purify and determine the radiochemical purity of [ 68 Ga]Ga-DOTA-TOC was essentially the same as that used by our group 33 with some adjustments. A solution of 210 ± 5 mg HEPES (Sigma-Aldrich) dissolved in 1 mL of deionized water was transferred into a reaction vial which contained the peptide DOTA-TOC previously dissolved in water.…”

“…PET studies were performed in an Argus PET/CT (SEDECAL) scanner. The procedure used was as described by our group 33 . Briefly, PET studies (energy window 250-700 keV and 30 min static acquisition) and CT studies (voltage 45 kV, current 150 μA, 8 shots, 360 projections, and standard resolution)…”