Abstract
Abstract Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where multiple populations of phenotypically different cells exist and contribute differentially to tumor dynamics. This tumor is characterized by a very low 2- year survival rate, high metastatic rates, and rapid acquisition of chemoresistance. Beyond first-line chemotherapy, targeted treatment options are scarce, and none take in to consideration the complex genetics of the tumor. The heterogeneous nature of this tumor makes it difficult to study and to treat, as current attempts to understand tumor dynamics use a bulk approach that averages the contribution of all cells within a tumor. This work uses a cellular barcoding lineage tracing approach combined with single-cell RNA sequencing (scRNA-seq) to understand tumor heterogeneity and evolution of SCLC in both a xenograft of human SCLC cell lines and an in vivo system using a genetically modified mouse model with alterations in the same driver genes as the majority of humans with SCLC. Tumors are sampled pre-growth, post-growth and metastasis, and pre- and post- chemotherapy. By paring the barcode populations that exist in samples over time, in metastasis, or in chemoresistance, a clonal evolution map of growth, metastasis, and chemoresistance can be generated, based on shared barcodes and convergent or divergent transcriptomic profiles. In validation of scRNA-seq data, we have identified the cancer testis antigens (CTA) PAGE5 and GAGE2A as markers of chemoresistance in human SCLC. CTAs have been successfully targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC. In mouse tumors, we have identified an AP-1-high population of early tumor cells that are maintained throughout the course of the disease. The knowledge gained in this work will pave the way for the identification of new therapeutic targets for SCLC. Citation Format: Hannah Wollenzien, Yohannes Afeworki, Michael S. Kareta. Transcriptional profiling of tumor heterogeneity and chemoresistance in small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A005.
Published Version
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