Identification and quantification of senescent cell types by lamin B1 and HMGB1 in Actinic keratosis lesions

Abstract

Actinic keratosis (AK), also known as solar keratosis, are thick, scaly or crusty skin commonly found on older, fair-skinned individuals due to chronic exposure to ultraviolet radiation (UVR) from sunlight. Premalignant AK is an incipient form of squamous cell carcinoma (SCC) [ [1] Carpenter P.M. Linden K.G. McLaren C.E. Li K.T. Arain S. Barr R.J. et al. Nuclear morphometry and molecular biomarkers of actinic keratosis, sun-damaged, and nonexposed skin. Cancer Epidemiol. Biomark. Prev. 2004; 13: 1996-2002 PubMed Google Scholar ]. UVR is also a potent inducer of cellular senescence, a state of irreversible growth arrest that is essential during embryonic development and tissue repair [ 2 Wang A.S. Dreesen O. Biomarkers of cellular senescence and skin aging. Front. Genet. 2018; Crossref Scopus (134) Google Scholar , 3 Fitsiou E. Pulido T. Campisi J. Alimirah F. Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging. J. Invest. Dermatol. 2021; 141: 1119-1126 Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar ]. Senescent cells accumulate in UV-induced skin pathologies and premalignant lesions [ 4 Collado M. Gil J. Efeyan A. Guerra C. Schuhmacher A.J. Barradas M. Benguría A. Zaballos A. Flores J.M. Barbacid M. Beach D. Serrano M. Tumour biology: senescence in premalignant tumours. Nature. 2005; 436: 642 Crossref PubMed Scopus (1128) Google Scholar , 5 Ivanov A. Pawlikowski J. Manoharan I. Van Tuyn J. Nelson D.M. Rai T.S. Shah P.P. Hewitt G. Korolchuk V.I. Passos J.F. Wu H. Berger S.L. Adams P.D. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 2013; 202: 129-143 Crossref PubMed Scopus (283) Google Scholar , 6 Wang A.S. Ong P.F. Chojnowski A. Clavel C. Dreesen O. Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin. Sci. Rep. 2017; 7 Google Scholar ] and express a number of biomarkers, including senescence associated-β-galactosidase (SA-β-gal) activity, up-regulation of cell cycle regulators such as p53, p21WAF1 and p16INK4a, and increased secretion of cytokines, chemokines and growth factors, collectively termed as senescence-associated secretory phenotype (SASP) [ 2 Wang A.S. Dreesen O. Biomarkers of cellular senescence and skin aging. Front. Genet. 2018; Crossref Scopus (134) Google Scholar , 3 Fitsiou E. Pulido T. Campisi J. Alimirah F. Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging. J. Invest. Dermatol. 2021; 141: 1119-1126 Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar ]. Due to technical limitations and cell type specific differences, it remains challenging to adequately quantify senescent cells within complex tissues such as human skin. To circumvent these limitations, we and others identified lamin B1 and high mobility group box 1 (HMGB1) as novel senescence markers in vitro and in vivo. Lamin B1 levels decrease in various skin cell types in vitro during replicative, UV- and oncogene-induced senescence [ 6 Wang A.S. Ong P.F. Chojnowski A. Clavel C. Dreesen O. Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin. Sci. Rep. 2017; 7 Google Scholar , 7 Dreesen O. Chojnowski A. Ong P.F. Zhao T.Y. Common J.E. Lunny D. Lane E.B. Lee S.J. Vardy L.A. Stewart C.L. Colman A. Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. J. Cell Biol. 2013; 200: 605-617 Crossref PubMed Scopus (142) Google Scholar , 8 Freund A. Laberge R.-M. Demaria M. Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell. 2012; 23: 2066-2075 Crossref PubMed Scopus (440) Google Scholar ], and in pre-neoplastic naevi [ [5] Ivanov A. Pawlikowski J. Manoharan I. Van Tuyn J. Nelson D.M. Rai T.S. Shah P.P. Hewitt G. Korolchuk V.I. Passos J.F. Wu H. Berger S.L. Adams P.D. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 2013; 202: 129-143 Crossref PubMed Scopus (283) Google Scholar ] and chronologically-aged human skin in vivo [ [7] Dreesen O. Chojnowski A. Ong P.F. Zhao T.Y. Common J.E. Lunny D. Lane E.B. Lee S.J. Vardy L.A. Stewart C.L. Colman A. Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. J. Cell Biol. 2013; 200: 605-617 Crossref PubMed Scopus (142) Google Scholar ], whilst HMGB1 was diminished in senescent fibroblasts in vitro [ [9] Davalos A.R. Kawahara M. Malhotra G.K. Schaum N. Huang J. Ved U. Beausejour C.M. Coppe J.P. Rodier F. Campisi J. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 2013; 201: 613-629 Crossref PubMed Scopus (231) Google Scholar ] and in aged skin in vivo [ [10] Victorelli S. Lagnado A. Halim J. Moore W. Talbot D. Barrett K. Chapman J. Birch J. Ogrodnik M. Meves A. Pawlikowski J.S. Jurk D. Adams P.D. Heemst D. Beekman M. Slagboom P.E. Gunn D.A. Passos J.F. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J. 2019; 38e101982 Crossref PubMed Scopus (58) Google Scholar ]. In this study, we aim to use lamin B1 and HMGB1 as biomarkers to rapidly detect and quantify senescent cell types in AK lesions in vivo.