Clonal populations of a human TNBC model display significant functional heterogeneity and divergent growth dynamics in distinct contexts

Intratumoral heterogeneity has been described for various tumor types and models of human cancer, and can have profound effects on tumor progression and drug resistance. This study describes an in-depth analysis of molecular and functional heterogeneity among subclonal populations (SCPs) derived fro...

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Bibliographic Details
Published in:Oncogene Vol. 41; no. 1; pp. 112 - 124
Main Authors: Kuiken, Hendrik J., Dhakal, Sabin, Selfors, Laura M., Friend, Chandler M., Zhang, Tian, Callari, Maurizio, Schackmann, Ron C. J., Gray, G. Kenneth, Crowdis, Jett, Bhang, Hyo-eun C., Baslan, Timour, Stegmeier, Frank, Gygi, Steven P., Caldas, Carlos, Brugge, Joan S.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 03.01.2022
Nature Publishing Group
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Animals
Apoptosis
Breast cancer
Cancer
Cell Biology
Cell culture
Copy number
Divergence
Drug resistance
Genetic Heterogeneity
Human Genetics
Humans
Interferon
Internal Medicine
Medicine
Medicine & Public Health
Mice
Microenvironments
Mutation
Oncology
Propagation
Proteomes
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - pathology
Tumor cell lines
Tumor Microenvironment - genetics
Tumor suppressor genes
Tumors
Xenografts
ISSN:0950-9232, 1476-5594, 1476-5594
Online Access:Get full text
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Summary:Intratumoral heterogeneity has been described for various tumor types and models of human cancer, and can have profound effects on tumor progression and drug resistance. This study describes an in-depth analysis of molecular and functional heterogeneity among subclonal populations (SCPs) derived from a single triple-negative breast cancer cell line, including copy number analysis, whole-exome and RNA sequencing, proteome analysis, and barcode analysis of clonal dynamics, as well as functional assays. The SCPs were found to have multiple unique genetic alterations and displayed significant variation in anchorage independent growth and tumor forming ability. Analyses of clonal dynamics in SCP mixtures using DNA barcode technology revealed selection for distinct clonal populations in different in vitro and in vivo environmental contexts, demonstrating that in vitro propagation of cancer cell lines using different culture conditions can contribute to the establishment of unique strains. These analyses also revealed strong enrichment of a single SCP during the development of xenograft tumors in immune-compromised mice. This SCP displayed attenuated interferon signaling in vivo and reduced sensitivity to the antiproliferative effects of type I interferons. Reduction in interferon signaling was found to provide a selective advantage within the xenograft microenvironment specifically. In concordance with the previously described role of interferon signaling as tumor suppressor, these findings suggest that similar selective pressures may be operative in human cancer and patient-derived xenograft models.
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HJK and SD performed all experiments with help from CMF and JC. LMS performed all of the bioinformatics, with exception of the gene expression analysis of PDX tumors, which was performed by MC in the laboratory of CC, and the copy number analysis, which was performed in the laboratory of TB. The mass spectrometry analyses were performed by TZ in the laboratory of SPG. The CyTOF analysis was performed by RCJS and GKG. HCB and FS provided the ClonTracer constructs and protocols for the analysis of the DNA barcode experiments. HJK and JSB generated the first draft of the manuscript and all authors contributed to the revisions.
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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-021-02075-y