Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model
Open accessAbstract
Monitoring cancer and aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse (p16(LUC)), which faithfully reports expression of p16(INK4a), a tumor suppressor and aging biomarker. Lifelong assessment of luminescence in p16(+/LUC) mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression of p16(INK4a) with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death. In 14 of 14 tested tumor models, expression of p16(LUC) was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities. Activation of p16(INK4a) was noted in the emerging neoplasm and surrounding stromal cells. This work suggests that p16(INK4a) activation is a characteristic of all emerging cancers, making the p16(LUC) allele a sensitive, unbiased reporter of neoplastic transformation.
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Mouse models of melanoma and human nevi show accumulation of SA-β-gal+-CDKN2A+ foci.
“Mouse models of melanoma and human nevi (both oncogene driven) show accumulation of SA-β-gal+–CDKN2A+ foci224,225.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [224]
The Results section (“p16LUC Signals Cancer”; page unavailable) reports focal p16INK4a-promoter activity in an oncogene-driven mouse melanoma model. It does not establish that those foci are SA-β-gal-positive, and the cited paper does not report the claimed foci in human nevi. (LLM, conf=0.85)
Experimental — accuracy not yet measuredp16 is considered the best marker of senescent cells.
“p16 is considered the best marker of senescent cells, and its expression is upregulated in many tissues during ageing [10 -12].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [12]
The Discussion calls p16INK4a expression “one of the best in vivo markers of cellular senescence,” supporting its standing as a strong marker. It does not identify p16 as the single best marker, and it notes that expression can also reflect tissue insults unrelated to senescence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAgeing is associated with the steady accumulation of senescent cells.
“Furthermore, as the most important risk factor for cancer, ageing is associated with the steady accumulation of senescent cells [10 -12]”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [12]
The Results section reports a sustained increase in p16INK4a expression with age and describes it as a marker of cellular senescence. The Discussion cautions, however, that this increase may reflect stresses other than senescence, so the paper does not establish a steady accumulation of senescent cells themselves. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSenescent cells accumulate due to various in vivo stresses during aging.
“Senescent cells have been observed to accumulate due to various in vivo stresses during the aging process (4–6).”
From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [5]
p16 expression is upregulated in many tissues during ageing.
“p16 is considered the best marker of senescent cells, and its expression is upregulated in many tissues during ageing [10 -12].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [12]
p16INK4a is a widely accepted marker of ageing and cellular senescence.
“This evidence has established p16INK4a as a widely-accepted marker of ageing and cellular senescence [81,82].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [81]
In vivo, the best currently available models for senescent cell detection are reporter-harbouring transgenic mice (p16-LUC, p16 tdTom) and transgenic mouse strains used for selective senescent cell removal (INK-ATTAC, p16-3MR).
“In vivo, the best currently available models for senescent cell detection are reporter-harbouring transgenic mice (p16-LUC, p16 tdTom)199,200 and transgenic mouse strains used for selective senescent cell removal (INK-ATTAC, p16-3MR).201”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [200]
In p16-reporter mice across transgenic autochthonous, transplanted and spontaneous tumour models, early neoplastic events induce stromal senescence often much earlier than tumours become palpable.
“With a number of different cancer models in the p16-reporter mouse, including transgenic autochthonous, transplanted and spontaneous tumours, the authors showed that early neoplastic events induce stromal senescence often much earlier than the tumours became palpable.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [124]
Stromal senescence activated by neoplastic events is generally tumorigenic, based on similar findings across different tumour models.
“these remarkably similar findings across different tumour models suggest that stromal senescence activated by neoplastic events is generally tumorigenic.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [124]
p16Ink4a expression is essentially undetectable in young and healthy tissues.
“The expression of p16Ink4a is essentially undetectable in young and healthy tissues, but p16Ink4a+ cells accumulate in many aged or diseased tissues.18,19,21,22,23,28”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [21]
p16Ink4a+ cells accumulate in many aged or diseased tissues.
“The expression of p16Ink4a is essentially undetectable in young and healthy tissues, but p16Ink4a+ cells accumulate in many aged or diseased tissues.18,19,21,22,23,28”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [21]
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Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A
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Self-citationUnraveling Adipocytes and Cancer Links: Is There a Role for Senescence?
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- Authors
- Burd, C. E., Sorrentino, J. A., Clark, K. S., Darr, D. B., Krishnamurthy, J., Deal, A. M., Bardeesy, N., Castrillon, D. H., Beach, D. H., & Sharpless, N. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Harvard University (US)
- Queen Mary University of London (GB)
- Corresponding author
- Sharpless, Norman E.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 152
- Issue
- 1-2
- Pages
- 340-351
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3718011
- OpenAlex
- W1988233144
- Cited by
- 419
- References
- 71
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 36 · 2023: 35 · 2022: 42 · 2021: 50 · 2020: 31 · 2019: 39 · 2018: 37 · 2017: 23 · 2016: 25 · 2015: 16 · 2014: 19 · 2013: 18
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Glenn Foundation for Medical Research
- University of Texas Southwestern Medical Center
- National Institutes of Health (5r01ag024379-15, AG024379)
- National Institute on Aging (AG024379, R01-AG024379, R00AG036817, K99AG036817, AG036817)
- National Cancer Institute (CA137181, CA163896, R01CA137181, R01CA163896, P30CA016086)
- National Institute of Environmental Health Sciences (T32ES007126)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p16INK4a, tumor suppressor, aging, cellular senescence, cancer detection, oncogenic transformation, stromal cells, in vivo imaging, aging biomarkers
- MeSH terms
- Aging, Animals, Cell Transformation, Neoplastic, Female, Luciferases, Neoplasms, Wounds and Injuries, Biomarkers, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Mice, Gene Knock-In Techniques
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