Abstract IA07: Influence of cancer initiation on tumor progression in SCLC

The vast majority of cancer patients die from metastatic disease, but the molecular and cellular mechanisms that drive metastatic progression often remain poorly understood. Small cell lung cancer (SCLC) is a neuroendocrine form of lung cancer and one of the most metastatic and lethal cancers. Most SCLC patients are usually first diagnosed when they already have metastatic disease, and SCLC tumors are thus thought to acquire metastatic ability early in the course of tumor development. However, how early events shape the evolution and metastatic progression of SCLC is largely unknown. We will present evidence, using genetically engineered mouse models of SCLC, that distinct mechanisms drive metastatic progression depending on the cell of origin. In one mouse model, we found that tumors gain metastatic ability through amplification of the transcription factor Nfib; this amplification is accompanied by a striking opening of the chromatin at many sites in the genome. In the second model, metastatic progression is not associated with Nfib-driven chromatin alterations. Gene expression profiling studies reveal distinct mechanisms of metastatic progression in the two groups, as well as markers predictive of the two metastatic paths. Our data indicate that Nfib-independent metastases arise from pulmonary neuroendocrine cells. These observations demonstrate that the identity of tumor-initiating cells can determine the molecular mechanisms of tumor evolution. Citation Format: Dian Yang, Monte M. Winslow, Julien Sage. Influence of cancer initiation on tumor progression in SCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA07.