Using Single-Cell Rna-Seq Approaches To Decipher Heterogeneity In Autochthonous Mouse Models Of Small Cell Lung Cancer

Small cell lung cancer (SCLC) is one of the most aggressive cancer types, and patients in clinic usually (u003e60% cases) present with metastasis. Current therapies for SCLC have not changed from 1980, and they include a combination therapy of cisplatin and etoposide. Most patients relapse after initial response, and the 5-year survival for extensive stage SCLC is 2%. One possible explanation for the failure of conventional and targeted therapies in cancers is the cellular heterogeneity that exists within tumors. Thus, understanding phenotypic heterogeneity at the single-cell level can be leveraged to predict mechanisms of resistance, which enables the design of effective combination therapies. In this project, we used as a model system an autochthonous mouse model of human SCLC, in which we deleted p53, RB, and p130. We collected multiple primary tumors, circulating tumor cells (CTC), and lymph node (proximal site) and liver (distant site) metastases from the same mouse, and across different mice. These samples were collected at the stage that should correspond to the limited/extensive stage of human SCLC, which is most commonly seen in clinic. Then we used single-cell RNA-seq (sc-RNAseq) methods to define and understand transcriptional heterogeneity in these samples. Furthermore, we aimed to understand the evolutionary relationships between primary tumors, CTCs, lymph node and liver metastases using different computational approaches such as diffusion maps. Further defining and functionally annotating transcriptional heterogeneity will help us better understand the disease, and find the new Achilles heel for targeting. Note: This abstract was not presented at the conference. Citation Format: Nemanja Despot Marjanovic, Sheng Rong Ng, Aviv Regev, Tyler Jacks. Using single-cell RNA-seq approaches to decipher heterogeneity in autochthonous mouse models of small cell lung cancer [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 A24.