Cellular senescence in precancer lesions and early-stage cancers

Xen Ping Hoi; Mary M Stangis; Sarah E Glass; Jin-Hee Kim; Seung Woo Kang; W Nathaniel Brennen; Ziyi Li; William M Grady; Srinivasan Yegnasubramanian; Peter Kuhn; Costas A Lyssiotis; Akiko Sagara; Martha J Shrubsole; Humam Kadara; Ying Yuan; Robert J Coffey; Ken S Lau; Angelo M De Marzo; Anirban Maitra; Jimin Min; Ming Yu; Keith S Chan; TBEL Consortium

doi:10.1016/j.ccell.2025.10.006

Cellular senescence in precancer lesions and early-stage cancers

Cancer Cell. 2025 Nov 6:S1535-6108(25)00447-7. doi: 10.1016/j.ccell.2025.10.006. Online ahead of print.

Authors

Xen Ping Hoi¹, Mary M Stangis², Sarah E Glass³, Jin-Hee Kim⁴, Seung Woo Kang⁵, W Nathaniel Brennen⁶, Ziyi Li⁷, William M Grady⁸, Srinivasan Yegnasubramanian⁹, Peter Kuhn¹⁰, Costas A Lyssiotis¹¹, Akiko Sagara¹², Martha J Shrubsole¹³, Humam Kadara¹⁴, Ying Yuan⁷, Robert J Coffey¹⁵, Ken S Lau¹⁶, Angelo M De Marzo¹⁷, Anirban Maitra¹⁸, Jimin Min¹⁹, Ming Yu²⁰, Keith S Chan²¹; TBEL Consortium

Affiliations

¹ Department of Urology, Dr. Mary and Ron Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
² University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
³ Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁵ Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁶ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Molecular Radiation Science Division, Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁰ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA.
¹¹ Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
¹² Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA.
¹³ Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
¹⁵ Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
¹⁶ Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁸ Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA; Department of Pathology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA; Department of Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA.
¹⁹ Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA; Department of Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA. Electronic address: jimin.min@nyulangone.org.
²⁰ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: myu@fredhutch.org.
²¹ Department of Urology, Dr. Mary and Ron Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. Electronic address: kschan@houstonmethodist.org.

PMID: 41202812
DOI: 10.1016/j.ccell.2025.10.006

Abstract

Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.