Abstract 1242: Single cell multiomic map reveals regulatory landscape of human brain metastases

Abstract Capturing comprehensive brain metastasis landscape is critical to the establishment of effective anti-tumor strategies. This study took advantage of single-cell multiomics sequencing to profile the molecular and cellular dynamics in tumor cells and associated microenvironment during brain metastasis. Among different primary cancer types, our data suggest that there are conserved yet distinct tumor cell subpopulations, governed by specific changes in gene expression, chromatin accessibility and tumor-stroma interactions. We characterized the conserved tumor subpopulations of brain metastasis with features of: (1) dormancy, (2) enhanced translation and migration, (3) cell death and (4) high proliferation rate. Dormant tumor cells in brain metastasis appear to limit cell-cell interactions with the surrounding microenvironment. In line with previous observations, dormant cells exhibit distinct stimulation for interferon, oxidative phosphorylation and HIPPO signaling. Despite a pronounced cell plasticity, trajectory analysis uncovered a cell progression pattern and its major sequential states and driving genes. Importantly, the tumor trajectory provides new insights into the regulatory landscape controlling the transition from dormant to proliferating tumor cells. Our findings also point to a valuable use of matched isolated circulating tumor cells and cell-free DNA to map the molecular and cellular dynamics of brain metastases. This work demonstrated that despite a pronounced intratumoral heterogeneity, brain metastases present conserved tumor subpopulations regardless of the patient and primary type. A novel and key finding in this study is the multiomics characterization of the regulatory landscape shaping human brain metatastases. Thus, we believe further understanding of these key regulatory elements could lead to novel tumor targets with broad translational potential. Citation Format: Remi Klotz, Alexis Zukowski, Mohamed Kamal, Frank Attenelo, Srinivas Ramachandran, Min Yu. Single cell multiomic map reveals regulatory landscape of human brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1242.