Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis

Yuning J. Tang, Jianguo Huang, Hidetoshi Tsushima, Ga I. Ban, Hongyuan Zhang, Kristianne M. Oristian, Vijitha Puviindran, Nerissa Williams, Xiruo Ding, Jianhong Ou, Sin Ho Jung, Chang Lung Lee, Yiqun Jiao, Benny J. Chen, David G. Kirsch, Benjamin A. Alman

Research output: Contribution to journalArticle

Abstract

Cellular heterogeneity is frequently observed in cancer, but the biological significance of heterogeneous tumor clones is not well defined. Using multicolor reporters and CRISPR-Cas9 barcoding, we trace clonal dynamics in a mouse model of sarcoma. We show that primary tumor growth is associated with a reduction in clonal heterogeneity. Local recurrence of tumors following surgery or radiation therapy is driven by multiple clones. In contrast, advanced metastasis to the lungs is driven by clonal selection of a single metastatic clone (MC). Using RNA sequencing (RNA-seq) and in vivo assays, we identify candidate suppressors of metastasis, namely, Rasd1, Reck, and Aldh1a2. These genes are downregulated in MCs of the primary tumors prior to the formation of metastases. Overexpression of these suppressors of metastasis impair the ability of sarcoma cells to colonize the lungs. Overall, this study reveals clonal dynamics during each step of tumor progression, from initiation to growth, recurrence, and distant metastasis.

Original languageEnglish
Pages (from-to)2837-2850.e5
JournalCell Reports
Volume28
Issue number11
DOIs
Publication statusPublished - Sep 10 2019

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tang, Y. J., Huang, J., Tsushima, H., Ban, G. I., Zhang, H., Oristian, K. M., ... Alman, B. A. (2019). Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis. Cell Reports, 28(11), 2837-2850.e5. https://doi.org/10.1016/j.celrep.2019.08.029