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| Status |
Public on Apr 02, 2024 |
| Title |
Progressive Senescence Programs Elicit Intrinsic Vulnerability to Ageing-related Cancer |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Cancer incidence escalates exponentially with advancing age, the mechanism of which remains obscure. Here we built up a chronological molecular clock at the single cell level for the mammary stem cell enriched population to depict the physiological ageing dynamics. We found the mammary ageing process was asynchronous and progressive, determined by the relative proportions of four distinct cellular states. The mammary ageing was initiated by a light senescence state with elevated NFkb, P53 signals, followed by a deep senescence state with reduced NFkb, P53 and enhanced PI3K-Akt-mTOR, Wnt, Notch and pluripotency activities succumb to cancer predisposition. Both of these senescence programs were regulated by a master mammary stem cell factor Bcl11b through modulation of multiple stress, longevity and pluripotency associated pathways. Depletion of Bcl11b triggered morphological, functional and molecular ageing-like phenotypes, and drastically enhanced DMBA-induced tumor formation. We further screened out a drug TPCA-1 that can elevate Bcl11b activity, rejuvenate mammary cells transcriptomically and significantly reduce the ageing-related cancer incidence. Our findings established a molecular portrait of progressive mammary cell ageing and elucidated the regulatory network bridging mammary ageing and cancer predisposition that can be modulated to control the cancer initiation, which has potential implications in management of cancer prevalence.
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| Overall design |
Single cell RNA profiles of mammary gland basal cells from different age, Bcl11b ko mice and mammary gland tumor
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| Web link |
https://www.nature.com/articles/s41467-024-49106-2
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| Contributor(s) |
Bai H, Liu X, Lin M, Meng Y, Tang R, Guo Y, Li N, F.Clarke M, Cai S |
| Citation(s) |
38886378 |
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| Submission date |
Jan 28, 2022 |
| Last update date |
Jun 18, 2024 |
| Contact name |
Shang Cai |
| E-mail(s) |
caishang@westlake.edu.cn
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| Organization name |
Westlake University
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| Department |
School of Life Science
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| Lab |
Stem Cell and Cancer Laboratory
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| Street address |
Shilongshan Road No.18, Cloud Town, Xihu District
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| City |
HangZhou |
| State/province |
ZheJiang |
| ZIP/Postal code |
310013 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (43)
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| Relations |
| BioProject |
PRJNA801627 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE195647_Barcode.txt.gz |
662 b |
(ftp)(http) |
TXT |
| GSE195647_RAW.tar |
14.7 Mb |
(http)(custom) |
TAR (of TSV) |
| GSE195647_bclrb12_IgG12_peaks.narrowPeak.gz |
22.7 Kb |
(ftp)(http) |
NARROWPEAK |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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