Abstract 985: Is the transcriptome of primary and metastatic cancers closer to their origin or target tissues

Abstract

Abstract Introduction: Most cancer deaths are caused by metastasis, yet understanding how metastatic cancers adapt from their origin tissues to their target tissues remains a fundamental scientific and clinical challenge. To date, no studies have systematically analyzed the transcriptomic similarity of metastatic cancers to their target tissues in a genome wide manner. Here, we ask if the overall gene expression of primary and metastatic tumors is closer to their tissue of origin or closer to their target tissue? Next, we aim to identify the key pathways in metastatic tumors whose gene expression becomes markedly closer to their target than primary tissue of origin. Methods: We analyzed the expression profiles of: (a) primary tumors of 9 cancer types, which have metastasized to the liver, lung, or brain (TCGA data, n = 306), (b) metastatic tumors of 12 cancer types (MET500 collection, n = 194) and (c) their origin and target normal tissue samples (GTEx, n = 5,663). We computed the similarity (Euclidean distance) between the expression profiles of the tumors (either primary or metastasis) to the mean expression of their corresponding normal tissue of origin and target tissues, termed their transcriptomic distance (TD). For each tumor sample’s expression profile (either primary tumor or metastasis), we compute the ratio of its TD to the tissue of origin over its TD to the target tissue to get its TD ratio. Results: 1) We find that while most primary tumors are more similar to the tissue of origin than to the target tissues, there is a shift in expression patterns in metastatic tumors towards their target. 2) Across cancer types that metastasize to the liver, cell cycle and growth pathways are significantly transcriptomically closer to the tissue of origin; while the expression of pathways related to more specialized liver cellular functions, such as coagulation and bile acid metabolism are becoming significantly closer to the liver. 3) We tested our key findings by analyzing a matched cohort of primary breast cancers and metastasis samples, reassuringly finding that they overall recapitulate the key results emerging from the non-matched analysis. The key pathways altered when metastasizing to four target tissues (liver, lung, ovary, skin) are adipogenesis, fatty acid metabolism, coagulation, xenobiotic metabolism, and bile acid metabolism. Conclusions: Quite surprisingly, this the first systematic analysis comparing the landscape of primary and metastatic transcriptional alterations of the same cancer type, providing a genome wide view of how cancers adapt to new environments during metastasis. The systematic identification of the specific pathways whose expression shifts towards the target tissues in metastatic tumors provides important leads to their potential targeting. Citation Format: Camilo Calvo-Alcañiz, Padma S. Rajagopal, Sanju Sinha, Fiorella Schischlik, Antonios Papanicolau-Sengos, Nishanth Ulhas Nair, Eytan Ruppin. Is the transcriptome of primary and metastatic cancers closer to their origin or target tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 985.