Author ORCID Identifier

0000-0003-3698-6724

Date of Graduation

5-2026

Document Type

Dissertation (PhD)

Program Affiliation

Quantitative Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Nicholas Navin

Committee Member

Wenyi Wang

Committee Member

Ann Killary

Committee Member

Savitri Krishnamurthy

Committee Member

Alastair Thompson

Committee Member

Linghua Wang

Abstract

Ductal carcinoma in situ (DCIS) is a preinvasive breast cancer in which cancer cells remain confined within the lumen of ducts. With the adoption of mammography, DCIS diagnoses have risen significantly, with approximately 50,000 new cases each year in the U.S. While 10-30% of DCIS patients progress to invasive disease (IDC) within the next 10 years, the lack of reliable biomarkers to predict DCIS recurrence leads to overtreatment, with almost all patients undergoing aggressive surgery, radiotherapy and chemotherapy. To better understand DCIS initiation and progression, we performed single-cell and spatial profiling of DCIS and IDC tissues. To overcome key limitations in spatial analysis, we first developed a computational tool, CellTrek, that directly maps single cells onto tissue sections. Applying CellTrek to DCIS samples, we found distinct cancer subclonal spatial architectures and immune cell distribution. Next, to establish a baseline for comparison, we constructed a human breast cell atlas from normal breast tissues, identifying 12 major cell types and 58 cell states with distinct spatial organization. Building on these foundational resources, we uncovered reprogrammed basal cells, vascular cells and fibroblasts that encircled the DCIS lesions. Notably, only lipo-macrophages and interferon T cells infiltrated DCIS regions, as well as the formation of tertiary lymphoid structures adjacent to lesions. Furthermore, DCIS cancer cells showed upregulated cell cycling and interferon signaling programs, while reducing cell adhesion, RNA processing, cell growth regulation and secretion pathways. Together, our data highlight extensive microenvironmental remodeling in DCIS that persists in invasive progression, providing new insights for risk stratification and targeted therapy development.

Keywords

breast cancer, DCIS, single cell RNA sequencing, spatial transcriptomics, tumor microenvironment

Download

Available for download on Sunday, April 18, 2027

Share

COinS