Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Tang, YJ; Huang, J; Tsushima, H; Ban, GI; Zhang, H; Oristian, KM; Puviindran, V; Williams, N; Ding, X; Ou, J; Jung, S-H; Lee, C-L; Jiao, Y; Chen, BJ; Kirsch, DG; Alman, BA

Published Date

  • September 10, 2019

Published In

Volume / Issue

  • 28 / 11

Start / End Page

  • 2837 - 2850.e5

PubMed ID

  • 31509746

Pubmed Central ID

  • 31509746

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2019.08.029

Language

  • eng

Conference Location

  • United States