TY - JOUR
T1 - Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis
AU - Tang, Yuning J.
AU - Huang, Jianguo
AU - Tsushima, Hidetoshi
AU - Ban, Ga I.
AU - Zhang, Hongyuan
AU - Oristian, Kristianne M.
AU - Puviindran, Vijitha
AU - Williams, Nerissa
AU - Ding, Xiruo
AU - Ou, Jianhong
AU - Jung, Sin Ho
AU - Lee, Chang Lung
AU - Jiao, Yiqun
AU - Chen, Benny J.
AU - Kirsch, David G.
AU - Alman, Benjamin A.
N1 - Funding Information:
This study was supported by a grant from the National Cancer Institute of the NIH (R01CA183811 to B.A.A.). The authors thank Ms. Consuelo Mendoza for helping with image analysis; Dr. Michael Cook and Lynn Martinek from the Duke University Flow Cytometry Core for flow cytometry support; Dr. David Corcoran from the Duke Center for Genomic and Computational Biology for assistance with analysis of RNA-seq and performing GSEA analysis; and Dr. Kouros Owzar and team from the Duke Cancer Institute for input on bioinformatics. D.G.K. and B.A.A. conceived the project. Y.J.T. D.G.K. and B.A.A. designed the experiments. Y.J.T. performed the experiments with assistance from J.H. H.T. N.W. H.Z. G.I.B. V.P. and K.M.O. J.H. helped with CRISPR-Cas9 barcoding experiments. H.T. K.M.O. and H.Z. assisted with histology. K.M.O. helped with cell work. X.D. and S.-H.J. performed biostatistics analysis with Y.J.T. Bioinformatics analysis for RNA-seq are performed by the Duke Center for Genomic and Computational Biology, and J.O. and C.-L.L. assisted with isolation and analysis of CTCs. B.J.C. and Y.J. provided expertise for intravital microscopy. D.G.K. and B.A.A. supervised the work. Y.J.T. D.G.K. and B.A.A. jointly wrote the manuscript with feedback from the other authors. The authors declare no competing interests.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/9/10
Y1 - 2019/9/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2019.08.029
DO - 10.1016/j.celrep.2019.08.029
M3 - Article
C2 - 31509746
AN - SCOPUS:85071832052
SN - 2211-1247
VL - 28
SP - 2837-2850.e5
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -
