Abstract IA34: Targeting cellular heterogeneity in lung adenocarcinoma

Abstract

Cancer arises from a single cell through a series of acquired mutations, and gradually develops into a complex tissue comprising phenotypically heterogeneous societies of cancer cells. The phenotype, or state, of each tumor cell is influenced by multiple cell-autonomous and cell-extrinsic factors; the diversity of these cellular states poses a challenge for effective cancer therapies. We characterized the evolution of transcriptomes at the single-cell level in genetically engineered murine lung tumors driven by oncogenic Kras. Tumor progression was accompanied by a dramatic increase in cellular heterogeneity, which was further exacerbated upon deletion of the p53 tumor suppressor, allowing tumor progression into advanced adenocarcinomas. This heterogeneity was manifested by the emergence of de-differentiated or transdifferentiated populations, the activation of latent developmental or regenerative programs, as well as heterogeneous activation of signaling pathways. Surprisingly, similar heterogeneous populations emerged in independent tumors irrespective of considerable intertumoral differences in genetic copy number alterations, suggesting a remarkable degree of convergence to achieve a common evolutionary endpoint. We used these data to computationally model cell-state transitions. Finally, treatment of the lung tumors with chemotherapy enabled the identification of cellular states associated with intrinsic sensitivity or resistance. These results associate tumor progression with increasing transcriptional heterogeneity. The identification of unique gene expression programs in cancer cell subpopulations provides a path towards reducing cellular heterogeneity in cancer. Citation Format: Nemanja Marjanovic, Matan Hofree, David Canner, Marianna Trakala, Katherine Wu, Olivia Smith, Jonathan Kim, Angelika Amon, Aviv Regev, Tyler Jacks, Tuomas Tammela. Targeting cellular heterogeneity in lung adenocarcinoma [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 IA34.