Abstract IA06: Driver mutations and cell-of-origin as critical factors determining the phenotypic characteristics of thoracic tumor subtypes

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-05, Vol.78 (10_Supplement), p.IA06-IA06
• Main Authors: Berns, Anton, Semenova, Ekaterina, Ferone, Giustina, Vries, Hilda de, Badhai, Jitendra, Kwon, Min-chul, Sutherland, Kate, Bombardelli, Lorenzo, Bhaskaran, Rajith, Song, Ji-Ying
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.MOUSEMODELS17-IA06

We have generated mouse models for specific lung tumors and mesothelioma. These were based on the conditional somatic (in)activation of tumor suppressor genes and oncogenes. By using viruses driving Cre recombinase from specific promoters, we could achieve both sporadic and cell-type specific switching of the conditional alleles allowing us to address the importance of the target cell in the development of specific tumor subtypes. We made the following observations. Small cell lung cancer (SCLC) development was fully dependent on the inactivation of Rb in conjunction with loss of p53. This neuroendocrine tumor could be most efficiently induced by targeting neuroendocrine cells using an Ad5-CGRP-Cre virus. However, when Rb and p53 were inactivated in combination with overexpression of L-myc, a gene frequently found amplified in both human and mouse, we noted additional tumors with a more peripheral location (more precisely at the bronchiolar-alveolar junction region) and with a less aggressive phenotype, but only when these tumors were induced by an Ad5-CMV-Cre virus. Since the latter tumors were strongly positive for neuroendocrine markers including CGRP, this indicates that the latter tumor subtype originated from a cell with no or very low CGRP expression and therefore different from the neuroendocrine cell targeted by Ad5-CGRP-Cre. The cell type giving rise to this tumor is not yet defined. Nevertheless, the different phenotypic characteristics of this tumor—that shows many of the features of SCLC—likely also have consequences for its prognosis and response to therapy. In testing a number of different combinations of lesions to induce squamous cell carcinoma (SCC), we found that development of SCC strongly depended on the overexpression of Sox2. Biallelic inactivation of Pten and Cdkn2a;Cdkn2b;p19Arf in combination with Sox2 overexpression promoted SCC at high penetrance but after a relatively long latency period. Phenotypically mouse SCC closely resembled human SCC, showing a very similar immunophenotyped, indicating that this is largely commanded by the tumor subtype. Interestingly, SCC could be induced at the same extend by activating the aforementioned genetic lesions in Basal, Club, and Alveolar type II cells (AT2). When targeting the latter two cell subtypes, they went through a dedifferentiation/transdifferentiation process with the concomitant loss and gain of transient cell markers; e.g., when targeting AT2 cells, the cells would lose SPC expre