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Single-Cell Transcriptomic Analysis of Mammary Tumors Reveals Distinct Patterns of Hierarchical and Subtype Heterogeneity

54 Pages Posted: 17 Jan 2019 Sneak Peek Status: Under Review

See all articles by Syn Kok Yeo

Syn Kok Yeo

University of Cincinnati - Department of Cancer Biology

Xiaoting Zhu

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics; University of Cincinnati - Department of Electrical Engineering and Computer Science

Takako Okamoto

University of Cincinnati - Department of Cancer Biology

Mingang Hao

University of Cincinnati - Department of Cancer Biology

Long Jason Lu

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics; University of Cincinnati - Department of Electrical Engineering and Computer Science

Jun-Lin Guan

University of Cincinnati - Department of Cancer Biology

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Abstract

Breast cancer stem cells (BCSCs) contribute to intra-tumoral heterogeneity and therapeutic resistance. However, the binary concept of universal BCSCs co-existing with bulk tumor cells is over-simplified. Through single-cell RNA-sequencing, we found that Neu, PyMT, BRCA1-null, and 4T1 mammary tumors each corresponded to a spectrum of minimally overlapping cell differentiation states without a universal BCSC population. Instead, our analyses revealed that these tumors contained distinct lineage-specific BCSCs and this is reflective of the self-sustaining capabilities of lineage-specific stem/progenitor cells in the mammary epithelial hierarchy. By understanding the respective tumor hierarchies, we were able to identify CD14 as a BCSC marker in the Neu tumor. Additionally, single-cell breast cancer subtype stratification revealed the co-existence of multiple breast cancer subtypes within tumors. Collectively, our findings emphasize the need to account for lineage-specific BCSCs and the hierarchical composition within breast tumors, as these heterogenous sub-populations can have differential therapeutic susceptibilities.

Keywords: Breast cancer, Cancer stem cells, Single-cell, Intra-tumoral heterogeneity, CD14

Suggested Citation

Kok Yeo, Syn and Zhu, Xiaoting and Okamoto, Takako and Hao, Mingang and Jason Lu, Long and Guan, Jun-Lin, Single-Cell Transcriptomic Analysis of Mammary Tumors Reveals Distinct Patterns of Hierarchical and Subtype Heterogeneity (January 16, 2019). Available at SSRN: https://ssrn.com/abstract=3316799 or http://dx.doi.org/10.2139/ssrn.3316799
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Syn Kok Yeo (Contact Author)

University of Cincinnati - Department of Cancer Biology

Cincinnati, OH 45267
United States

Xiaoting Zhu

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics

Cincinnati, OH 45229
United States

University of Cincinnati - Department of Electrical Engineering and Computer Science

2901 Woodside Drive
Cincinnati, OH
United States

Takako Okamoto

University of Cincinnati - Department of Cancer Biology

Cincinnati, OH 45267
United States

Mingang Hao

University of Cincinnati - Department of Cancer Biology

Cincinnati, OH 45267
United States

Long Jason Lu

Cincinnati Children's Hospital Medical Center - Division of Biomedical Informatics

Cincinnati, OH 45229
United States

University of Cincinnati - Department of Electrical Engineering and Computer Science

2901 Woodside Drive
Cincinnati, OH
United States

Jun-Lin Guan

University of Cincinnati - Department of Cancer Biology

Cincinnati, OH 45267
United States

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