Investigating The Rare Aneuploid Cells in Normal Breast and Therapeutic Resistance in Triple Negative Breast Cancer Using Single Cell Genomics

<p>Aneuploid epithelial cells are common in breast cancer, however their presence in normal breast tissues is not well understood. To address this question, we applied single cell DNA sequencing to profile copy number alterations (CNAs) in 83,206 epithelial cells from breast tissues of 49 healthy women and single cell DNA&ATAC co-assays to 19 women. Our data shows that all women harbored rare aneuploid epithelial cells (median 3.19%) that increased with age. Many aneuploid epithelial cells (median 82.22%) in normal breast tissues underwent clonal expansions and harbored CNAs reminiscent of invasive breast cancers (gains of 1q, losses of 10q, 16q and 22q). Co-assay profiling showed that the aneuploid cells were associated with the two luminal epithelial lineages, while spatial mapping showed that they localized in ductal and lobular structures with normal histopathology. Collectively, these data show that even healthy women have clonal expansions of rare aneuploid epithelial cells in their breast tissues. Aside from the aneuploid evolution in normal tissue, we next investigated the tumor evolution and tumor heterogeneity in triple-negative breast cancer (TNBC) under the chemo-resistance context. TNBC is an aggressive subtype that is frequently treated with chemotherapy, but only half of the patients have a complete response. Here, we performed single cell transcriptomic analysis of 427,857 cells from treatment-naïve samples of 101 patients with TNBC treated with neoadjuvant chemotherapy. We classified the TNBC cancer cells into four major patient-level archetypes that further exhibited intratumoral heterogeneity in 13 different metaprograms. The TNBC tumor microenvironment (TME) consisted of 49 distinct immune and stromal cell states, many of which were reprogrammed relative to normal breast tissues from disease-free women. In contrast to previous studies, our data highlight the importance of macrophage subtypes and cancer cell metaprograms for interferon signaling, HLA expression and cell cycle activity that were associated with chemotherapy response.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2024

Authors dc:creator

• Lin, Yiyun
• <p>https://orcid.org/0000-0002-9277-3048</p>

Contributors dc:contributor

• Nicholas Navin
• Ken Chen
• Khandan Keyomarsi

• single cell genomics
• breast cancer
• tumor evolution
• TME
• tumor initiation
• Bioinformatics
• Computational Biology
• Genomics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1400

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2457