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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 28 Issue 11 Pg. 2837-2850.e5 (09 10 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 31509746 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• GPI-Linked Proteins
• Luminescent Proteins
• Reck protein, mouse
• Aldehyde Dehydrogenase 1 Family
• Aldh1a2 protein, mouse
• Retinal Dehydrogenase
• Rasd1 protein, mouse
• ras Proteins

Topics

• Aldehyde Dehydrogenase 1 Family (genetics, metabolism)
• Animals
• Cell Lineage
• Clonal Evolution (genetics)
• Clone Cells (cytology, metabolism)
• GPI-Linked Proteins (genetics, metabolism)
• Luminescent Proteins
• Mice
• Mice, Nude
• Neoplasm Recurrence, Local (genetics, metabolism)
• RNA-Seq
• Retinal Dehydrogenase (genetics, metabolism)
• Sarcoma (genetics, metabolism, pathology, secondary)
• Transcriptome (genetics)
• ras Proteins (genetics, metabolism)