Abstract 2482: Inferring cancer type-specific patterns of metastatic spread using Metient

Abstract Reconstructing the metastatic spread of a cancer from molecular sequencing of primary and metastatic tumors is a challenging problem with broad applications in clinical cancer research. In particular, this problem often yields multiple solutions, which current methods resolve with ad hoc criteria that assume the most likely patterns of metastatic spread - thus sidestepping a core question of metastasis research. Here we introduce Metient, a statistical method which proposes multiple possible hypotheses of metastatic spread in a cohort of patients and rescores these hypotheses using independent data on genetic distance of metastasizing clones and organotropism. Metient is more accurate and is up to 50x faster than the current state-of-the-art, making it the first method capable of scaling to lineage tracing datasets with thousands of cells while providing a multi-hypothesis approach to metastatic spread. In a reanalysis of metastasis in 169 patients based on 490 tumors, Metient automatically identifies cancer type-specific trends of metastatic dissemination in melanoma, high-risk neuroblastoma, and non-small cell lung cancer. Its reconstructions often align with semi-manual expert analyses but frequently reveal more plausible migration histories, including those with metastasis-to-metastasis seeding. Furthermore, Metient’s heightened sensitivity suggests that polyclonal seeding is far more common than previously reported. Together, these findings challenge existing assumptions about metastatic spread, enhance our understanding of cancer type-specific metastasis, and offer insights that could inform future clinical treatment strategies of metastasis. Citation Format: Divya Koyyalagunta, Karuna Ganesh, Quaid Morris. Inferring cancer type-specific patterns of metastatic spread using Metient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2482.