Midkine As a Driver of Age-related Changes and Increase in Mammary Tumorigenesis

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2024 Oct 4

PMID 39366375

Authors

Pengze Yan

Ernesto Rojas Jimenez

Zheqi Li

Triet Bui

Marco Seehawer

Jun Nishida

Pierre Foidart

Laura E Stevens

Yingtian Xie

Miguel Munoz Gomez

So Yeon Park

Henry W Long

Kornelia Polyak

Affiliations

Soon will be listed here.

Abstract

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.

Citing Articles

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

Angarola B, Sharma S, Katiyar N, Kang H, Nehar-Belaid D, Park S Nat Aging. 2024; 5(1):122-143.

PMID: 39587369 PMC: 11754115. DOI: 10.1038/s43587-024-00751-8.

References

Stuart T, Srivastava A, Madad S, Lareau C, Satija R . Single-cell chromatin state analysis with Signac. Nat Methods. 2021; 18(11):1333-1341. PMC: 9255697. DOI: 10.1038/s41592-021-01282-5. View

Ibusuki M, Fujimori H, Yamamoto Y, Ota K, Ueda M, Shinriki S . Midkine in plasma as a novel breast cancer marker. Cancer Sci. 2009; 100(9):1735-9. PMC: 11159736. DOI: 10.1111/j.1349-7006.2009.01233.x. View

Elyahu Y, Monsonego A . Thymus involution sets the clock of the aging T-cell landscape: Implications for declined immunity and tissue repair. Ageing Res Rev. 2020; 65:101231. DOI: 10.1016/j.arr.2020.101231. View

Hinohara K, Wu H, Vigneau S, McDonald T, Igarashi K, Yamamoto K . KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer Cell. 2018; 34(6):939-953.e9. PMC: 6310147. DOI: 10.1016/j.ccell.2018.10.014. View

Franklin R, Liao W, Sarkar A, Kim M, Bivona M, Liu K . The cellular and molecular origin of tumor-associated macrophages. Science. 2014; 344(6186):921-5. PMC: 4204732. DOI: 10.1126/science.1252510. View

Berdyshev G, Korotaev G, Boiarskikh G, Vaniushin B . [Nucleotide composition of DNA and RNA from somatic tissues of humpback and its changes during spawning]. Biokhimiia. 1967; 32(5):988-93. View

Chaffer C, Weinberg R . Cancer cell of origin: spotlight on luminal progenitors. Cell Stem Cell. 2010; 7(3):271-2. PMC: 2941878. DOI: 10.1016/j.stem.2010.08.008. View

Kang T, Yau C, Wong C, Sanborn J, Newton Y, Vaske C . A risk-associated Active transcriptome phenotype expressed by histologically normal human breast tissue and linked to a pro-tumorigenic adipocyte population. Breast Cancer Res. 2020; 22(1):81. PMC: 7395362. DOI: 10.1186/s13058-020-01322-6. View

Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C . Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020; 588(7836):124-129. PMC: 7752134. DOI: 10.1038/s41586-020-2975-4. View

10.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

11.

Gail M, Brinton L, Byar D, Corle D, Green S, Schairer C . Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989; 81(24):1879-86. DOI: 10.1093/jnci/81.24.1879. View

12.

Selman M, Pardo A . Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology. Ageing Res Rev. 2021; 70:101393. DOI: 10.1016/j.arr.2021.101393. View

13.

Bidoli E, Virdone S, Hamdi-Cherif M, Toffolutti F, Taborelli M, Panato C . Worldwide Age at Onset of Female Breast Cancer: A 25-Year Population-Based Cancer Registry Study. Sci Rep. 2019; 9(1):14111. PMC: 6773713. DOI: 10.1038/s41598-019-50680-5. View

14.

Kumar T, Nee K, Wei R, He S, Nguyen Q, Bai S . A spatially resolved single-cell genomic atlas of the adult human breast. Nature. 2023; 620(7972):181-191. PMC: 11443819. DOI: 10.1038/s41586-023-06252-9. View

15.

Velentzis L, Freeman V, Campbell D, Hughes S, Luo Q, Steinberg J . Breast Cancer Risk Assessment Tools for Stratifying Women into Risk Groups: A Systematic Review. Cancers (Basel). 2023; 15(4). PMC: 9953796. DOI: 10.3390/cancers15041124. View

16.

Peto J . Cancer epidemiology in the last century and the next decade. Nature. 2001; 411(6835):390-5. DOI: 10.1038/35077256. View

17.

Browaeys R, Saelens W, Saeys Y . NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods. 2019; 17(2):159-162. DOI: 10.1038/s41592-019-0667-5. View

18.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

19.

Neumaier E, Rothhammer V, Linnerbauer M . The role of midkine in health and disease. Front Immunol. 2023; 14:1310094. PMC: 10720637. DOI: 10.3389/fimmu.2023.1310094. View

20.

Lu J, Ahmad R, Nguyen T, Cifello J, Hemani H, Li J . Heterogeneity and transcriptome changes of human CD8 T cells across nine decades of life. Nat Commun. 2022; 13(1):5128. PMC: 9436929. DOI: 10.1038/s41467-022-32869-x. View