Abstract SY10-02: Mouse models for (non) small cell lung cancer: Heterogeneity and cell of origin

Abstract

Abstract Small cell lung cancer (SCLC) is one of the most lethal human malignancies, due to its high metastatic potential and chemo-resistance upon relapse. Using the Rb1flox/flox;Trp53flox/flox mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells, characterized by mesenchymal and neuroendocrine markers. These cells had a common origin as they shared specific genomic aberrations. Crosstalk between mesenchymal and neuroendocrine cells can endow the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating functional tumor properties. We have further studied which genes might be critical for this process. We could show that in particular the activation of the transcription factor PEA3 in neuroendocrine cells was instrumental although not sufficient to confer full metastatic potential to the neuroendocrine tumor cells. Interestingly, these neuroendocrine cells can convert into the mesenchymal component by Ras pathway activation, suggesting that these cell types might interconvert and mediate paracrine signaling. This interconversion also raises the question of the cell-of-origin of this tumor. To investigate this in more detail, we inactivated Trp53 and Rb1 in distinct subsets of cells in the adult lung by targeting Cre-recombinase expression to Clara (CC10 positive), neuroendocrine (CGRP positive), and alveolar type 2 (SPC positive) cells using adenoviral vectors harboring cell-type specific promoters driving Cre recombinase. Using these cell-type-specific Cre expression adenoviruses we could show that inactivation of Trp53 and Rb1 can efficiently transform neuroendocrine (CGRP-positive) and to a lesser extent alveolar type II (SPC-positive) cells leading to SCLC. In contrast CC10-expressing clara cells were largely resistant to transformation. The results clearly indicate that neuroendocrine cells serve as the predominant cell of origin of SCLC. A different cell type specificity was found when a Lox-Stop-Lox (LSL-)mutant-Kras driven non-small-cell lung cancer (NSCLC) model was used to reveal the cell-of-origin of NSCLC. In this case we noted a significant difference whether LSL-mutant-Kras mice or LSL-mutant-Kras;Trp53flox/flox mice were infected with the various virus constructs. In LSL-mutant-Kras mice alveolar type II cells appeared the most effective target for inducing adenomas whereas in LSL-mutant-Kras;Trp53flox/flox mice multiple cell types gave effectively rise to adenomas and adenocarcinomas. Our data indicate that both cell type specific features and the nature of the oncogenic lesion(s) are critical factors in determining the tumor initiating capacity of lung (progenitor) cells to give rise to the various lung cancer subtypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY10-02. doi:1538-7445.AM2012-SY10-02