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
Affiliations
Yuning J. Tang
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Jianguo Huang
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA
Hidetoshi Tsushima
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Ga I. Ban
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Hongyuan Zhang
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA
Kristianne M. Oristian
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
Vijitha Puviindran
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Nerissa Williams
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA
Xiruo Ding
Department of Biostatics and Bioinformatics, Duke University, Durham, NC, USA
Jianhong Ou
Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA; Regeneration Next Initiative, Duke University, Durham, NC, USA
Sin-Ho Jung
Department of Biostatics and Bioinformatics, Duke University, Durham, NC, USA
Chang-Lung Lee
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA
Yiqun Jiao
Duke Cancer Institute, Duke University, Durham, NC, USA
Benny J. Chen
Duke Cancer Institute, Duke University, Durham, NC, USA; Regeneration Next Initiative, Duke University, Durham, NC, USA
David G. Kirsch
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA; Duke Cancer Institute, Duke University, Durham, NC, USA; Regeneration Next Initiative, Duke University, Durham, NC, USA; Corresponding author
Benjamin A. Alman
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA; Duke Cancer Institute, Duke University, Durham, NC, USA; Regeneration Next Initiative, Duke University, Durham, NC, USA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Corresponding author
Summary: 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. : Tang et al. demonstrate that distinct clonal architecture underlies different stages of tumor progression, from tumor initiation, local recurrence after therapy, to advanced metastasis. Keywords: clonal evolution, cancer metastasis, suppressors of metastasis, sarcoma, tumor heterogeneity, lineage tracing
