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

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Publication Year:
2021
Authors:
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 Muschen, Akil A Merchant, Rong Lu
PubMed ID:
34764253
Funding Grants:
Public Summary:
Cancer is often resistant to treatment due to the variability of cancer cells within a tumor. Even with advanced genetic and molecular analysis, it's challenging to understand how these variations affect cancer behavior. This study introduces a new approach that combines single-cell gene expression analysis with tracking cancer cell growth and response to treatment using barcode technology. In leukemia, they found that cells with different gene expression patterns responded uniquely to chemotherapy. They also discovered that in some cases, leukemia cells expanded only in specific areas of the bone marrow with distinct gene expression. This integrated system offers insights into the complex and diverse nature of cancer, aiding in the understanding of its progression and resistance to treatment.
Scientific 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.