Adaptation and selection shape clonal evolution of tumors during residual disease and recurrence.

Abstract

The survival and recurrence of residual tumor cells following therapy constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during relapse. We use cellular barcoding to monitor clonal dynamics during tumor recurrence in vivo. We find that clonal diversity decreases during tumor regression, residual disease, and recurrence. The recurrence of dormant residual cells follows several distinct routes. Approximately half of the recurrent tumors exhibit clonal dominance with a small number of subclones comprising the vast majority of the tumor; these clonal recurrences are frequently dependent upon Met gene amplification. A second group of recurrent tumors comprises thousands of subclones, has a clonal architecture similar to primary tumors, and is dependent upon the Jak/Stat pathway. Thus the regrowth of dormant tumors proceeds via multiple routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.

• Authors: Andrea Walens, Jiaxing Lin, Jeffrey S Damrauer, Brock McKinney, Ryan Lupo, Rachel Newcomb, Douglas B Fox, Nathaniel W Mabe, Jeremy Gresham, Zhecheng Sheng, Alexander B Sibley, Tristan De Buysscher, Hemant Kelkar, Piotr A Mieczkowski, Kouros Owzar, James V Alvarez
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 5017 (10 06 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 33024122 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Crizotinib
• ERBB2 protein, human
• Proto-Oncogene Proteins c-met
• Receptor, ErbB-2
• Doxycycline

Topics

• Animals
• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Crizotinib (pharmacology)
• Doxycycline (pharmacology)
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• High-Throughput Nucleotide Sequencing
• Humans
• Lung Neoplasms (pathology, secondary)
• Mice, Nude
• Neoplasm Recurrence, Local (drug therapy, genetics, pathology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics)
• Receptor, ErbB-2 (genetics)
• Single-Cell Analysis
• Xenograft Model Antitumor Assays