Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses

Humberto Contreras-Trujillo, Jiya Eerdeng, Samir Akre, Du Jiang, Jorge Contreras, Basia Gala, Mary C. Vergel-Rodriguez, Yeachan Lee, Aparna Jorapur, Areen Andreasian, Lisa Harton, Charles S. Bramlett, Anna Nogalska, Gang Xiao, Jae-Woong Lee, Lai N. Chan, Markus Müschen, Akil A. Merchant () and Rong Lu ()
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Humberto Contreras-Trujillo: University of Southern California
Jiya Eerdeng: University of Southern California
Samir Akre: University of Southern California
Du Jiang: University of Southern California
Jorge Contreras: University of Southern California
Basia Gala: University of Southern California
Mary C. Vergel-Rodriguez: University of Southern California
Yeachan Lee: University of Southern California
Aparna Jorapur: University of Southern California
Areen Andreasian: University of Southern California
Lisa Harton: University of Southern California
Charles S. Bramlett: University of Southern California
Anna Nogalska: University of Southern California
Gang Xiao: Yale University
Jae-Woong Lee: Yale University
Lai N. Chan: Yale University
Markus Müschen: Yale University
Akil A. Merchant: Cedars-Sinai Medical Center
Rong Lu: University of Southern California

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Cellular heterogeneity is a major cause of treatment resistance in cancer. Despite recent advances in single-cell genomic and transcriptomic sequencing, it remains difficult to relate measured molecular profiles to the cellular activities underlying cancer. Here, we present an integrated experimental system that connects single cell gene expression to heterogeneous cancer cell growth, metastasis, and treatment response. Our system integrates single cell transcriptome profiling with DNA barcode based clonal tracking in patient-derived xenograft models. We show that leukemia cells exhibiting unique gene expression respond to different chemotherapies in distinct but consistent manners across multiple mice. In addition, we uncover a form of leukemia expansion that is spatially confined to the bone marrow of single anatomical sites and driven by cells with distinct gene expression. Our integrated experimental system can interrogate the molecular and cellular basis of the intratumoral heterogeneity underlying disease progression and treatment resistance.

Date: 2021
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DOI: 10.1038/s41467-021-26771-1

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