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健康乳腺组织的综合单细胞衰老图谱揭示了衰老和癌症共有的表观基因组和转录组特征。

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

作者信息

Angarola Brittany L, Sharma Siddhartha, Katiyar Neerja, Kang Hyeon Gu, Nehar-Belaid Djamel, Park SungHee, Gott Rachel, Eryilmaz Giray N, LaBarge Mark A, Palucka Karolina, Chuang Jeffrey H, Korstanje Ron, Ucar Duygu, Anczukόw Olga

机构信息

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

The Jackson Laboratory, Bar Harbor, ME, USA.

出版信息

Nat Aging. 2025 Jan;5(1):122-143. doi: 10.1038/s43587-024-00751-8. Epub 2024 Nov 25.

DOI:10.1038/s43587-024-00751-8
PMID:39587369
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11754115/
Abstract

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated 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 and 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, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible 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.

摘要

衰老 是乳腺癌最大的风险因素；然而，与年龄相关的细胞和分子事件如何影响癌症的发生尚不清楚。在本研究中，我们以单细胞分辨率研究了衰老如何重塑小鼠乳腺的转录组和表观基因组程序，为衰老和癌症生物学提供了一个全面的资源。衰老的上皮细胞在代谢、促炎和癌症相关基因中表现出表观遗传和转录变化。衰老的基质细胞下调成纤维细胞标记基因，上调衰老和癌症相关成纤维细胞的标记。在免疫细胞中，不同的T细胞亚群（Gzmk、记忆性CD4、γδ）和M2样巨噬细胞随年龄增长而增加。空间转录组学揭示了衰老的免疫细胞和上皮细胞在原位的共定位。最后，我们在人类乳腺肿瘤中发现了衰老乳腺细胞的转录特征，提示衰老与癌症之间可能存在联系。总之，这些数据揭示了上皮细胞、免疫细胞和基质细胞在比例和细胞特性上的变化，可能影响细胞可塑性、衰老微环境和肿瘤形成风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ed/11754115/6735096263f0/43587_2024_751_Fig18_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ed/11754115/80da60214e37/43587_2024_751_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ed/11754115/22986f48dec7/43587_2024_751_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ed/11754115/2b2b8b3cd9f5/43587_2024_751_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ed/11754115/a8b93a431565/43587_2024_751_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ed/11754115/a9413bcfc4be/43587_2024_751_Fig17_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ed/11754115/6735096263f0/43587_2024_751_Fig18_ESM.jpg

相似文献

[1]
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[2]
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[3]
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[6]
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[8]
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引用本文的文献

[1]
The Role of Senescence, its Therapeutic Relevance and Clinical Implications in the Tumor Microenvironment.

Theranostics. 2025-7-28

[2]
Ageing, immune fitness and cancer.

Nat Rev Cancer. 2025-8-14

[3]
Beyond polarization: macrophage senescence in immunoregulation and cancer therapy.

Int J Biol Sci. 2025-6-23

[4]
Plasticity and Functional Heterogeneity of Cancer-Associated Fibroblasts.

Cancer Res. 2025-7-29

[5]
Investigating Transcriptional Age Acceleration in Inflammatory Skin Diseases.

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[6]
Single-cell analysis of gene regulatory networks in the mammary glands of P4HA1-knockout mice.

PLoS Genet. 2025-7-22

[7]
The Aging Microenvironment as a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.

bioRxiv. 2025-5-10

[8]
Reciprocal immune-epithelial interaction during breast cancer induction.

J Immunother Cancer. 2025-6-19

[9]
Transforming Cancer Therapy: Unlocking the Potential of Targeting Vascular and Stromal Cells in the Tumor Microenvironment.

Cancer Res. 2025-4-2

[10]
Immuno-oncology recapitulates ontogeny: Modern cell and gene therapy for cancer.

Mol Ther. 2025-5-7

本文引用的文献

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Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility.

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