Different Originating Cells Underlie Intertumoral Heterogeneity in Lung Neuroendocrine Tumors

Abstract

Studies in genetically engineered mouse models of neuroendocrine lung cancer suggest that differences in cells of origin underlie subtype variations in this class of cancers. These findings highlight the concept that the same driver mutations introduced into different cells of origin lead to tumors with the same histology but dramatically different metastatic programs and potentially different therapeutic responses. Cancer Discov; 8(10); 1216-8. ©2018 AACR See related article by Yang et al., p. 1316.

Figure 1.

Cell of origin in SCLC GEMMs influences tumor generation, genetic characteristics, and metastasis. Loss of TP53 and RB1 are defining mutations in SCLC. A, Mouse models for SCLC involve deleting Trp53, Rb1, and the Rb1-related Rbl2 (p130) by introduction of virus expressing Cre to the respiratory epithelium (4). Use of the CMV promoter directs Cre broadly in diverse lung cell types whereas the CGRP promoter directs Cre to rare NE cells in the proximal airways. B, Both models result in histologically similar primary NE tumors; however, the CMV-Cre model generates substantially more tumors. C, An additional distinction is that metastatic tumors arising from the different models have differential requirement for the transcription factor NFIB, and in comparison to metastases from CGRP-Cre–driven tumors, the CMV-Cre–driven tumors have a more neural developmental gene signature (1). How well these models represent variant subtypes seen in patient SCLC populations, and their distinctions in response to therapies, will have to await future analyses. Pale yellow cells indicate tumor cells that arise from lineage marker–negative cells that progress to a CGRP-positive, NE⁺ phenotype. These tumor cells have similarities to those arising from CGRP-positive cells but are not identical in gene expression and chromatin landscape.