Abstract PR-006: Brain metastases roadmap reveals conserved regulatory dynamics rooted in dormant tumor cells

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) epithelial to mesenchymal transition and (4) high proliferation rate. In line with previous observations, dormant cells exhibit distinct stimulation for interferon and oxidative phosphorylation. Furthermore, our data suggest that dormant tumor cells increase amino acids metabolism and antigen presentation by upregulating HLA class molecules. Stromal and tumor cells interaction network analysis predicted most active ligands that might shape intratumoral heterogeneity. For example, TGFβ signaling induced by immune cells and astrocytes is associated with tumor cell epithelial to mesenchymal transition. Additionally, results suggest the vascular endothelial niche supports brain metastasis proliferation. Interestingly, dormant tumor cells appear to limit cell-cell interactions with the surrounding microenvironment when compared to other tumor cells subpopulations. Despite pronounced cell plasticity, trajectory analysis uncovered a cell progression pattern and its major sequential states and driving genes. Notably, the trajectory embarked with dormant tumor cells at its root and ended with a prevalence of rapidly proliferating tumor cells. As cycling cancer cells arise, we observed a disruption in circadian rhythm regulators activities, indicating that altered circadian regulation may contribute to brain metastasis progression. This work demonstrated that despite a pronounced intratumoral heterogeneity, brain metastases present conserved tumor subpopulations regardless of the patient and primary type. Importantly, the tumor trajectory provides new insights into the regulatory landscape controlling the transition from dormant to proliferating tumor cells. A novel and key finding in this study is the multiomics characterization of the regulatory landscape shaping human brain metastases. Thus, we believe further understanding of these key regulatory elements could lead to novel tumor targets with broad translational potential. Citation Format: Remi Klotz, Yiru Jess Wang, Alexis Zukowski, Frank Attenelo, Srinivas Ramachandran, Min Yu. Brain metastases roadmap reveals conserved regulatory dynamics rooted in dormant tumor cells [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-006.