Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues

Sep 21, 2026

Metastasis drives most cancer-related deaths, yet how metastatic tumors reprogram from their origin to target tissues remains a key challenge. This study evaluates whether primary and metastatic tumors more closely resemble tissues of origin or target tissues using multi-cancer gene-expression profiles, including single-cell and bulk RNA sequencing. Primary tumors stay more similar to origin tissues, while metastases shift toward target tissues. Pathway analysis reveals metabolic and immune transcriptomic changes toward target tissues during metastasis, alongside higher cancer-hallmark activity in primary tumors.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Metastasis and molecular cascade

Metabolic and immune transcriptomic adaptation

Prior transcriptomic comparisons and organotropism

CANCER Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues Neel Sanghvi1,2†, Camilo Calvo-Alcañiz1†, Padma S. Rajagopal1, Stefano Scalera3, Valeria Canu3, Sanju Sinha1,4, Fiorella Schischlik1, Kun Wang1,5,6, Sanna Madan1,2, Eldad Shulman1, Antonios Papanicolau-Sengos7, Giovanni Blandino3, Eytan Ruppin1*, Nishanth Ulhas Nair1* Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to their target tissues remains a fundamental challenge. To address this, we assessed whether primary and metastatic tumors more closely resemble their tissues of origin or target tissues in terms of gene expression. We analyzed expression profiles from multiple cancer types and normal tissues, including single-cell and bulk RNA sequencing data from both paired and unpaired patient cohorts. Primary tumors were overall more transcriptomically similar to their tissues of origin, while metastases shifted toward their target tissues. However, pathwaylevel analysis highlighted critical metabolic and immune transcriptomic changes toward target tissues during metastasis in both primary and metastatic tumors. In addition, primary tumors exhibited higher activity in cancer hallmarks such as “Activating Invasion and Metastasis”when compared to metastases. This comprehensive analysis provides a transcriptome-wide view of the processes through which cancer tumors adapt to their metastatic environments before and after metastasis. copyright © 2024 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. Distributed under a creative commons Attribution license 4.0 (cc BY) . INTRODUCTION Most cancer deaths are caused by metastasis, a hallmark of cancer that remains poorly understood. The metastatic process, in which primary tumor cells adapt and travel from their origin tissue (OT) to target tissue(s) (TTs), is a complex cascade of molecular alterations (1) . Numerous studies have examined the molecular features of metastatic cancers, highlighting hallmarks such as cell motility and invasion, the ability to modulate the TT, phenotype plasticity, and the ability to colonize the TT (2). In particular, metabolic adaptations play an important role in metastases as they seed in their TT (3), including altered fatty acid metabolism and changes in energy supply to initiate and promote metastasis (4–7). Primary tumors, on the other hand, have been found to remain overall metabolically similar in their expression profiles to their normal OTs, although with some up-regulation of pathways such as nucleotide synthesis and glycolysis (8), suggesting different genomic rewiring during growth from metastases. Previous work has directly compared primary and metastatic tumors’ transcriptomics, identifying differentially expressed markers and metastatic alterations across various cancer types (3, 9, 10). Furthermore, genomic sequencing of 25,000 primary and metastatic tumors revealed higher chromosome instability, fractions of clonal mutations, and enrichments in drug resistance mechanisms in 1cancer Data Science laboratory (cDSl), national cancer institute (nci), national institutes of health (nih), Bethesda, MD, USA. 2Fischell Department of Bioengineering, University of Maryland, college Park, MD, USA. 3translational Oncology Research Unit, iRcSS Regina elena national cancer institute, via elio chianesi, Rome, italy. 4Sanford Burnham Prebys Medical Discovery institute, San Diego, cA, USA. 5Department of comparative Biosciences, University of illinois Urbana-champaign, Urbana, il, USA. 6Department of Bioengineering, University of illinois Urbanachampaign, Urbana, il, USA. 7laboratory of Pathology, national cancer institute (nci), national institutes of health (nih), Bethesda, MD, USA. *[corresponding author. email: eytan.ruppin@nih.gov

FAQs

How does the study compare primary and metastatic tumors to their tissues of origin and target tissues?

It assesses transcriptomic similarity using gene-expression profiles across multiple cancer types and normal tissues, leveraging single-cell and bulk RNA-seq data from paired and unpaired cohorts.

What overall shift is observed between primary tumors and metastases regarding tissue similarity?

Primary tumors are overall more similar to their tissues of origin, whereas metastases shift toward their target tissues in their gene-expression programs.

Which biological pathway changes are emphasized during metastasis?

Pathway-level analysis highlights critical metabolic and immune transcriptomic changes toward target tissues during metastasis in both primary and metastatic tumors.

Sep 21, 2026

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