Abstract IA013: A single-cell and spatial investigation of tumor and TME for DCIS

Abstract

Abstract Ductal carcinoma in situ (DCIS) is early-stage non-malignant breast cancer that tumor cells are confined to the lumens of ducts. Over 50,000 DCIS patients are diagnosed each year in the United States, however, less than half of DCIS will develop into invasive breast cancer (IBC), suggesting a risk of overtreatment for some DCIS patients. A comprehensive investigation of the molecular mechanisms of DCIS initiation and progression is urgently needed that can facilitate us stratifying the risk of DCIS invasion and design better intervention approaches. In this study, we conducted single-cell RNA-seq and spatial transcriptomics (ST) on DCIS and IBC samples (most estrogen receptor positive). We first inferred copy number aberrations (CNA) in these samples and found that DCIS and IBC shared the most copy number events while only marginal differences were identified. Tumor CNA subclones colocalized in different ductal regions from the ST data. Further, we applied a sample-wise non-negative matrix factorization (NMF) to identify robust gene expression metaprograms across tumor samples. On the ST data, we found these metaprograms also displayed distinct spatial patterns. For non-tumor cells in the TME, we sub-clustering them into cell states and identified that some cell states showed a gradual change along breast cancer initiation and progression. To recapitulate the tumor ecosystems, we also conducted an ecotype analysis in DCIS samples and identified that some ecotypes showed an increasing/decreasing trend in IBC patients. Further, tumor and TME ecotypes also showed spatially colocalizations based on our ST data. In summary, these results demonstrated that genomic signatures could hardly predict the DCIS progression while tumor metaprograms and TME ecotypes might serve as a potential risk stratification approach for DCIS patients. Citation Format: Runmin Wei, Siyuan He, Shanshan Bai, Emi Sei, Min Hu, Chandandeep Nagi, Brian Menegaz, Huma Javaid, Jelle Wesseling, Andrew Futreal, Alastair Thompson, Savitri Krishnamurthy, Nicholas Navin. A single-cell and spatial investigation of tumor and TME for DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA013.