Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer

Brittany Lynn Angarola; Siddhartha M. Sharma; Neerja Katiyar; Hyeon Gu Kang; Djamel Nehar-Belaid; Sung‐Hee Park; Rachel Gott; Giray Naim Eryilmaz; Mark A. LaBarge; Karolina Palucka; Jeffrey H. Chuang; Ron Korstanje; Duygu Ucar; Olga Anczuków

doi:10.1101/2023.10.20.563147

GenomicsbioRxivOct 20, 2023

Preprint

Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer

Brittany Lynn Angarola iD, Siddhartha M. Sharma iD, Neerja Katiyar iD, Hyeon Gu Kang iD, Djamel Nehar-Belaid iD, Sung‐Hee Park iD, Rachel Gott, Giray Naim Eryilmaz iD, Mark A. LaBarge iD, Karolina Palucka iD, Jeffrey H. Chuang iD, Ron Korstanje iD, Duygu Ucar iD, Olga Anczuków iD

Abstract

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. We investigate how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory, or cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, {gamma}{delta}) and M2-like macrophages expand with age. Spatial transcriptomics reveal co-localization of aged immune and epithelial cells in situ. Lastly, transcriptional signatures of aging mammary cells are found in human breast tumors, suggesting mechanistic links between aging and cancer. Together, these data uncover that epithelial, immune, and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk.

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