Transcriptomic analysis identifies organ-specific metastasis genes and pathways across different primary sites

• Lin Zhang,
• Ming Fan,
• Francesco Napolitano,
• Xin Gao,
• Ying Xu &
• Lihua Li

Journal of Translational Medicine volume 19, Article number: 31 (2021) Cite this article

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Abstract Background Metastasis is the most devastating stage of cancer progression and often shows a preference for specific organs.Methods To reveal the mechanisms underlying organ-specific metastasis, we systematically analyzed gene expression profiles for three common metastasis sites across all available primary origins. A rank-based method was used to detect differentially expressed genes between metastatic tumor tissues and corresponding control tissues. For each metastasis site, the common differentially expressed genes across all primary origins were identified as organ-specific metastasis genes.Results Pathways enriched by these genes reveal an interplay between the molecular characteristics of the cancer cells and those of the target organ. Specifically, the neuroactive ligand-receptor interaction pathway and HIF-1 signaling pathway were found to have prominent roles in adapting to the target organ environment in brain and liver metastases, respectively. Finally, the identified organ-specific metastasis genes and pathways were validated using a primary breast tumor dataset. Survival and cluster analysis showed that organ-specific metastasis genes and pathways tended to be expressed uniquely by a subgroup of patients having metastasis to the target organ, and were associated with the clinical outcome.Conclusions Elucidating the genes and pathways underlying organ-specific metastasis may help to identify drug targets and develop treatment strategies to benefit patients.

Background Metastasis is a fatal step in cancer progression and is the main cause of cancer-related deaths [1]. Tumor metastasis to different organs is not a random process but is known to show organ-specific preference [2]. Organ-specific metastasis was first described by the “seed and soil” theory proposed by Stephen Paget; according to the theory, certain tumors (the “seeds”) have specific affinity for particular organs (the “soil”) [3]. For instance, colon carcinomas usually metastasize to liver and lung but rarely to bone, brain, and kidneys. In contrast, breast carcinomas, frequently metastasize to most of these organs [4]. Recent discoveries indicate that molecular characteristics of cancer cells and their target tissues cooperate to determine the organ-specific metastasis observed for many tumors, greatly enhancing our understanding of the “seed and soil” theory [5]. Investigation of the mechanisms that mediate site-specific metastasis are likely to lead to the identification of new drug targets for therapy. For instance, targeting the expression of platelet-derived growth factor receptor signaling pathways in tumor-associated endothelial cells and pericytes could inhibit liver metastasis of colon carcinoma [6]. However, the mechanisms of organ-specific metastasis remain an intriguing but unanswered questions in cancer research.Gene expression profiles are widely used to explore organ-specific metastasis. Several groups have developed microarray-based diagnostic tools to determine a tumor’s site of origin [7, 8] or to predict metastasis sites [9]. For example, the Pathwork Diagnostics® is a well-studied and clinically validated microarray-based gene expression diagnostic test for determining tissue of origin [7, 8]. However, these studies did not elucidate the roles of signatures in the preferences of primary tumor types when spreading to specific distant sites. Several groups have worked on this question, mainly focusing on identifying genes that mediate metastases of one primary cancer type to particular sites [10,11,12] or whose expression in primary tumors correlates with metastatic recurrence [13]. However, to our knowledge, these markers tended to capture the diversity of primary cancer metastases, especially for breast cancer metastases [10,11,12, 14]. There has been a lack of systematic research on the commonality of molecular characteristics for different primary tumors metastasizing to the same target organ. Moreover, a well-designed dataset and schema of organ-specific metastasis gene identification are crucial for this type of analysis.In this study, we investigate organ-specific metastasis by examining gene expression signatures across different tumor types that metastasize to the same organ (e.g., comparing primary breast and lung tumors that both metastasize to the brain). For each metastasis site (brain, liver, or lung), at least two types of primary site were included in the integrated dataset. Then, a rank-based method was used to detect differentially expressed genes (DEGs) between metastatic tumor tissues and the corresponding control tissues. We focused on common DEGs and enriched pathways across all tissues of origin, and investigated these organ-specific metastasis genes and enriched pathways in breast primary tumors. Cluster analysis and survival analysis were used to test whether the organ-specific metastasis genes and pathways were expressed uniquely by a subgroup of patients with metastasis to the target organ, and whether they were associated with clinical outcomes. In conclusion, we present here an analysis to identify signatures that are specific to the common target organ rather than to diverse primary tumor tissue types. The delineation of the roles of these signatures in the interplay between cancer cells and the target organ will lead to a better understanding of organ-specific metastasis and its susceptibilities to treatment.

Metastatic sites may share many of the transcriptome of the original tumor. I do not think that your comparison between primary tumor and metastasis will lead you to identify metastogenes. Remember that metastasis can also originate further metastasis.