Abstract B100: Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues
Authors: Sanghvi Neel , Calvo-Alcañiz Camilo , Rajagopal Padma S , Sinha Sanju , Schischlik Fiorella , Wang Kun , Madan Sanna , Papanicolau-Sengos Antonios , Ruppin Eytan , Nair Nishanth Ulhas 
Published: December 2023

Abstract
Introduction. Over two-thirds of cancer-related deaths are due to metastasis. Here, we aim to determine the similarity of primary and metastatic cancers to their normal origin and target tissues in a genome-wide, pan-cancer manner. Studying a collection of bulk and single-cell RNA-seq datasets, we ask two fundamental questions: (1) Are primary and metastatic tumors transcriptomically more similar to the organ from which they originate or to the organ to which they metastasize? (2) Which specific pathways expressions remain akin to the origin tissue and which ones shift their expression towards their target tissues?
Methods. We analyzed the gene expression profiles of both paired and unpaired primary and metastatic tumor patient cohorts, studying single-cell, bulk-deconvolved, and bulk RNA-seq data. Overall, we used expression data from primary tumors of 11 cancer types marked as developing future metastases with a known target, and metastases of 14 cancer types with their corresponding non-cancerous origin and target tissue samples. To quantify the similarities between tumor samples and their origin and target tissues, we computed the Euclidean distance between their expression profiles, termed their transcriptomic distances, at both the whole-genome and pathway level.
Results. (1) In multiple bulk RNA-seq datasets, the expression patterns of metastases are markedly altered, becoming more similar to their target tissues than the tissues of origin. In stark contrast, primary tumors’ expressions remain more similar to their origin tissues. Metastases become superficially more transcriptomically similar to their target tissues than to other non-cancerous tissues. (2) Liver metastases’ expressions shift to express liver-specialized cellular functions such as bile acid metabolism and coagulation, while the cell cycle and growth pathways mainly change in a cancer type manner, maintaining their characteristic expression in the origin tissue. Adipogenesis and fatty acid metabolism are closer to the brain in both primary and brain-metastatic samples. (3) Reassuringly, when analyzing paired primary-metastases in deconvolved-bulk and single-cell cohorts, primary and metastatic tumor cells mirror the trends found in the bulk. Deconvolved breast cancer brain metastases show expression upregulation of adipogenesis and fatty acid metabolism, as well as oxidative phosphorylation pathways, reflecting the transcriptome of these pathways in the brain.
Conclusions. This first-of-its-kind systematic analysis of the expression landscape of primary tumors and metastases with respect to their healthy origin and target tissues provides a transcriptome-wide, pan-cancer view of cancer tumor adaptations to their metastatic niches. By highlighting these alterations across the bulk, deconvolved bulk, and single-cell levels, we identify pathways that are altered in the metastatic process to adapt to the transcriptomic landscape of their target tissues.
Citation Format: Neel Sanghvi, Camilo Calvo-Alcañiz, Padma S Rajagopal, Sanju Sinha, Fiorella Schischlik, Kun Wang, Sanna Madan, Antonios Papanicolau-Sengos, Eytan Ruppin, Nishanth Ulhas Nair. Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B100.