Aging involves tissue accumulation of senescent cells (SC) whose elimination through senolytic approaches may evoke organismal rejuvenation. SC also contribute to aging-associated pathologies including cancer, hence it is imperative to better identify and target SC. Here, we aimed to identify new cell-surface proteins differentially expressed on human SC. Besides previously reported proteins enriched on SC, we identified 78 proteins enriched and 73 proteins underrepresented in replicatively senescent BJ fibroblasts, including L1CAM, whose expression is normally restricted to the neural system and kidneys. L1CAM was: 1) induced in premature forms of cellular senescence triggered chemically and by gamma-radiation, but not in Ras-induced senescence; 2) induced upon inhibition of cyclin-dependent kinases by p16INK4a; 3) induced by TGFbeta and suppressed by RAS/MAPK(Erk) signaling (the latter explaining the lack of L1CAM induction in RAS-induced senescence); and 4) induced upon downregulation of growth-associated gene ANT2, growth in low-glucose medium or inhibition of the mevalonate pathway. These data indicate that L1CAM is controlled by a number of cell growth- and metabolism-related pathways during SC development. Functionally, SC with enhanced surface L1CAM showed increased adhesion to extracellular matrix and migrated faster. Our results provide mechanistic insights into senescence of human cells, with implications for future senolytic strategies.

Danish Cancer Society Research Center Copenhagen DK 2100 Denmark

Department of Genome Integrity Institute of Molecular Genetics of the ASCR Prague 14220 Czech Republic

Division of Genome Biology Department of Medical Biochemistry and Biophysics Karolinska Institute Stockholm Sweden

Institute of Chemistry Slovak Academy of Sciences Bratislava 84538 Slovakia

Institute of Molecular and Translational Medicine Palacky University Olomouc 77147 Czech Republic

Laboratory of Immunological and Tumour Models Institute of Molecular Genetics of the ASCR Prague 14220 Czech Republic

Laboratory of Molecular Therapy Institute of Biotechnology of the ASCR Prague 14220 Czech Republic

Zobrazit více v PubMed

Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016; 530:184–89. 10.1038/nature16932 PubMed DOI PMC

Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479:232–36. 10.1038/nature10600 PubMed DOI PMC

Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014; 15:482–96. 10.1038/nrm3823 PubMed DOI

Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. 2010; 12:676–85. 10.1038/ncb2070 PubMed DOI PMC

Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014; 31:722–33. 10.1016/j.devcel.2014.11.012 PubMed DOI PMC

Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005; 436:720–24. 10.1038/nature03890 PubMed DOI

Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006; 444:633–37. 10.1038/nature05268 PubMed DOI

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre’ M, Nuciforo PG, Bensimon A, Maestro R, Pelicci PG, d’Adda di Fagagna F. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444:638–42. 10.1038/nature05327 PubMed DOI

Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel ES, Lausch E, Christov K, Roninson IB. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 1999; 59:3761–67. PubMed

te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 2002; 62:1876–83. PubMed

Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T. A senescent cell bystander effect: senescence-induced senescence. Aging Cell. 2012; 11:345–49. 10.1111/j.1474-9726.2012.00795.x PubMed DOI PMC

Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc Natl Acad Sci USA. 2009; 106:17031–36. 10.1073/pnas.0905299106 PubMed DOI PMC

Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017; 8:14532. 10.1038/ncomms14532 PubMed DOI PMC

Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6:2853–68. 10.1371/journal.pbio.0060301 PubMed DOI PMC

Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013; 15:978–90. 10.1038/ncb2784 PubMed DOI PMC

Hubackova S, Krejcikova K, Bartek J, Hodny Z. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ‘bystander senescence’. Aging (Albany NY). 2012; 4:932–51. 10.18632/aging.100520 PubMed DOI PMC

Starr ME, Saito M, Evers BM, Saito H. Age-Associated Increase in Cytokine Production During Systemic Inflammation-II: The Role of IL-1β in Age-Dependent IL-6 Upregulation in Adipose Tissue. J Gerontol A Biol Sci Med Sci. 2015; 70:1508–15. 10.1093/gerona/glu197 PubMed DOI PMC

Hoenicke L, Zender L. Immune surveillance of senescent cells--biological significance in cancer- and non-cancer pathologies. Carcinogenesis. 2012; 33:1123–26. 10.1093/carcin/bgs124 PubMed DOI

Cudejko C, Wouters K, Fuentes L, Hannou SA, Paquet C, Bantubungi K, Bouchaert E, Vanhoutte J, Fleury S, Remy P, Tailleux A, Chinetti-Gbaguidi G, Dombrowicz D, et al. p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages. Blood. 2011; 118:2556–66. 10.1182/blood-2010-10-313106 PubMed DOI PMC

Fuentes L, Wouters K, Hannou SA, Cudejko C, Rigamonti E, Mayi TH, Derudas B, Pattou F, Chinetti-Gbaguidi G, Staels B, Paumelle R. Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype. Diabetologia. 2011; 54:3150–56. 10.1007/s00125-011-2324-0 PubMed DOI PMC

Bürrig KF. The endothelium of advanced arteriosclerotic plaques in humans. Arterioscler Thromb. 1991; 11:1678–89. 10.1161/01.ATV.11.6.1678 PubMed DOI

Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, Baker DJ, van Deursen JM, Campisi J, Elisseeff JH. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017; 23:775–81. 10.1038/nm.4324 PubMed DOI PMC

McCulloch K, Litherland GJ, Rai TS. Cellular senescence in osteoarthritis pathology. Aging Cell. 2017; 16:210–18. 10.1111/acel.12562 PubMed DOI PMC

Zhu F, Li Y, Zhang J, Piao C, Liu T, Li HH, Du J. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One. 2013; 8:e74535. 10.1371/journal.pone.0074535 PubMed DOI PMC

Kim KH, Chen CC, Monzon RI, Lau LF. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol. 2013; 33:2078–90. 10.1128/MCB.00049-13 PubMed DOI PMC

Sone H, Kagawa Y. Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia. 2005; 48:58–67. 10.1007/s00125-004-1605-2 PubMed DOI

Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, Johnson FB, Trojanowski JQ, Sell C, Torres C. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One. 2012; 7:e45069. 10.1371/journal.pone.0045069 PubMed DOI PMC

Chinta SJ, Lieu CA, Demaria M, Laberge RM, Campisi J, Andersen JK. Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson’s disease? J Intern Med. 2013; 273:429–36. 10.1111/joim.12029 PubMed DOI PMC

Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017; 7:165–76. 10.1158/2159-8290.CD-16-0241 PubMed DOI PMC

Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007; 8:729–40. 10.1038/nrm2233 PubMed DOI

Li Y, Galileo DS. Soluble L1CAM promotes breast cancer cell adhesion and migration in vitro, but not invasion. Cancer Cell Int. 2010; 10:34. 10.1186/1475-2867-10-34 PubMed DOI PMC

Fogel M, Mechtersheimer S, Huszar M, Smirnov A, Abu-Dahi A, Tilgen W, Reichrath J, Georg T, Altevogt P, Gutwein P. L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma. Cancer Lett. 2003; 189:237–47. 10.1016/S0304-3835(02)00513-X PubMed DOI

Bondong S, Kiefel H, Hielscher T, Zeimet AG, Zeillinger R, Pils D, Schuster E, Castillo-Tong DC, Cadron I, Vergote I, Braicu I, Sehouli J, Mahner S, et al. Prognostic significance of L1CAM in ovarian cancer and its role in constitutive NF-κB activation. Ann Oncol. 2012; 23:1795–802. 10.1093/annonc/mdr568 PubMed DOI

Chen DL, Zeng ZL, Yang J, Ren C, Wang DS, Wu WJ, Xu RH. L1cam promotes tumor progression and metastasis and is an independent unfavorable prognostic factor in gastric cancer. J Hematol Oncol. 2013; 6:43. 10.1186/1756-8722-6-43 PubMed DOI PMC

Tischler V, Pfeifer M, Hausladen S, Schirmer U, Bonde AK, Kristiansen G, Sos ML, Weder W, Moch H, Altevogt P, Soltermann A. L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer. Mol Cancer. 2011; 10:127. 10.1186/1476-4598-10-127 PubMed DOI PMC

Geismann C, Morscheck M, Koch D, Bergmann F, Ungefroren H, Arlt A, Tsao MS, Bachem MG, Altevogt P, Sipos B, Fölsch UR, Schäfer H, Müerköster SS. Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer. Cancer Res. 2009; 69:4517–26. 10.1158/0008-5472.CAN-08-3493 PubMed DOI

Tsutsumi S, Morohashi S, Kudo Y, Akasaka H, Ogasawara H, Ono M, Takasugi K, Ishido K, Hakamada K, Kijima H. L1 Cell adhesion molecule (L1CAM) expression at the cancer invasive front is a novel prognostic marker of pancreatic ductal adenocarcinoma. J Surg Oncol. 2011; 103:669–73. 10.1002/jso.21880 PubMed DOI

Kim YM, Byun HO, Jee BA, Cho H, Seo YH, Kim YS, Park MH, Chung HY, Woo HG, Yoon G. Implications of time-series gene expression profiles of replicative senescence. Aging Cell. 2013; 12:622–34. 10.1111/acel.12087 PubMed DOI

Martin MN, Saladores PH, Lambert E, Hudson AO, Leustek T. Localization of members of the gamma-glutamyl transpeptidase family identifies sites of glutathione and glutathione S-conjugate hydrolysis. Plant Physiol. 2007; 144:1715–32. 10.1104/pp.106.094409 PubMed DOI PMC

Yoon IK, Kim HK, Kim YK, Song IH, Kim W, Kim S, Baek SH, Kim JH, Kim JR. Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology. Exp Gerontol. 2004; 39:1369–78. 10.1016/j.exger.2004.07.002 PubMed DOI

Smith JR, Hayflick L. Variation in the life-span of clones derived from human diploid cell strains. J Cell Biol. 1974; 62:48–53. 10.1083/jcb.62.1.48 PubMed DOI PMC

Robles SJ, Adami GR. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene. 1998; 16:1113–23. 10.1038/sj.onc.1201862 PubMed DOI

Michishita E, Nakabayashi K, Suzuki T, Kaul SC, Ogino H, Fujii M, Mitsui Y, Ayusawa D. 5-Bromodeoxyuridine induces senescence-like phenomena in mammalian cells regardless of cell type or species. J Biochem. 1999; 126:1052–59. 10.1093/oxfordjournals.jbchem.a022549 PubMed DOI

Kim KS, Kang KW, Seu YB, Baek SH, Kim JR. Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev. 2009; 130:179–88. 10.1016/j.mad.2008.11.004 PubMed DOI

Yeo EJ, Hwang YC, Kang CM, Kim IH, Kim DI, Parka JS, Choy HE, Park WY, Park SC. Senescence-like changes induced by hydroxyurea in human diploid fibroblasts. Exp Gerontol. 2000; 35:553–71. 10.1016/S0531-5565(00)00108-X PubMed DOI

Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88:593–602. 10.1016/S0092-8674(00)81902-9 PubMed DOI

Grage-Griebenow E, Jerg E, Gorys A, Wicklein D, Wesch D, Freitag-Wolf S, Goebel L, Vogel I, Becker T, Ebsen M, Röcken C, Altevogt P, Schumacher U, et al. L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression. Mol Oncol. 2014; 8:982–97. 10.1016/j.molonc.2014.03.001 PubMed DOI PMC

Simova J, Sapega O, Imrichova T, Stepanek I, Kyjacova L, Mikyskova R, Indrova M, Bieblova J, Bubenik J, Bartek J, Hodny Z, Reinis M. Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines. Oncotarget. 2016; 7:54952–64. 10.18632/oncotarget.10712 PubMed DOI PMC

Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, Ranta F, Ullrich S, Mocikat R, et al. T-helper-1-cell cytokines drive cancer into senescence. Nature. 2013; 494:361–65. 10.1038/nature11824 PubMed DOI

Galanos P, Vougas K, Walter D, Polyzos A, Maya-Mendoza A, Haagensen EJ, Kokkalis A, Roumelioti FM, Gagos S, Tzetis M, Canovas B, Igea A, Ahuja AK, et al. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nat Cell Biol. 2016; 18:777–89. 10.1038/ncb3378 PubMed DOI PMC

Leontieva OV, Lenzo F, Demidenko ZN, Blagosklonny MV. Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells. Cell Cycle. 2012; 11:4642–49. 10.4161/cc.22937 PubMed DOI PMC

Schaefer AW, Kamiguchi H, Wong EV, Beach CM, Landreth G, Lemmon V. Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization. J Biol Chem. 1999; 274:37965–73. 10.1074/jbc.274.53.37965 PubMed DOI

Silletti S, Yebra M, Perez B, Cirulli V, McMahon M, Montgomery AM. Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion. J Biol Chem. 2004; 279:28880–88. 10.1074/jbc.M404075200 PubMed DOI

Yi YS, Baek KS, Cho JY. L1 cell adhesion molecule induces melanoma cell motility by activation of mitogen-activated protein kinase pathways. Pharmazie. 2014; 69:461–67. PubMed

Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr, Raman V, Zhen L, Mitzner WA, et al. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene. 2012; 31:1757–70. 10.1038/onc.2011.365 PubMed DOI PMC

Li M, Durbin KR, Sweet SM, Tipton JD, Zheng Y, Kelleher NL. Oncogene-induced cellular senescence elicits an anti-Warburg effect. Proteomics. 2013; 13:2585–96. 10.1002/pmic.201200298 PubMed DOI PMC

Gey C, Seeger K. Metabolic changes during cellular senescence investigated by proton NMR-spectroscopy. Mech Ageing Dev. 2013; 134:130–38. 10.1016/j.mad.2013.02.002 PubMed DOI

Maya-Mendoza A, Ostrakova J, Kosar M, Hall A, Duskova P, Mistrik M, Merchut-Maya JM, Hodny Z, Bartkova J, Christensen C, Bartek J. Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress. Mol Oncol. 2015; 9:601–16. 10.1016/j.molonc.2014.11.001 PubMed DOI PMC

Kretova M, Sabova L, Hodny Z, Bartek J, Kollarovic G, Nelson BD, Hubackova S, Luciakova K. TGF-β/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence. Cell Signal. 2014; 26:2903–11. 10.1016/j.cellsig.2014.08.029 PubMed DOI

Hubackova S, Kucerova A, Michlits G, Kyjacova L, Reinis M, Korolov O, Bartek J, Hodny Z. IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2. Oncogene. 2016; 35:1236–49. 10.1038/onc.2015.162 PubMed DOI

Chevrollier A, Loiseau D, Reynier P, Stepien G. Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism. Biochim Biophys Acta. 2011; 1807:562–67. 10.1016/j.bbabio.2010.10.008 PubMed DOI

Chevrollier A, Loiseau D, Chabi B, Renier G, Douay O, Malthièry Y, Stepien G. ANT2 isoform required for cancer cell glycolysis. J Bioenerg Biomembr. 2005; 37:307–16. 10.1007/s10863-005-8642-5 PubMed DOI

Giraud S, Bonod-Bidaud C, Wesolowski-Louvel M, Stepien G. Expression of human ANT2 gene in highly proliferative cells: GRBOX, a new transcriptional element, is involved in the regulation of glycolytic ATP import into mitochondria. J Mol Biol. 1998; 281:409–18. 10.1006/jmbi.1998.1955 PubMed DOI

Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH, Lee DJ, Chaft JE, Kris MG, Huse JT, Brogi E, Massagué J. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014; 156:1002–16. 10.1016/j.cell.2014.01.040 PubMed DOI PMC

Wang E. Are cross-bridging structures involved in the bundle formation of intermediate filaments and the decrease in locomotion that accompany cell aging? J Cell Biol. 1985; 100:1466–73. 10.1083/jcb.100.5.1466 PubMed DOI PMC

Nishio K, Inoue A. Senescence-associated alterations of cytoskeleton: extraordinary production of vimentin that anchors cytoplasmic p53 in senescent human fibroblasts. Histochem Cell Biol. 2005; 123:263–73. 10.1007/s00418-005-0766-5 PubMed DOI

Evangelou K, Lougiakis N, Rizou SV, Kotsinas A, Kletsas D, Muñoz-Espín D, Kastrinakis NG, Pouli N, Marakos P, Townsend P, Serrano M, Bartek J, Gorgoulis VG. Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging Cell. 2017; 16:192–97. 10.1111/acel.12545 PubMed DOI PMC

Biran A, Zada L, Abou Karam P, Vadai E, Roitman L, Ovadya Y, Porat Z, Krizhanovsky V. Quantitative identification of senescent cells in aging and disease. Aging Cell. 2017; 16:661–71. 10.1111/acel.12592 PubMed DOI PMC

Rathjen FG, Schachner M. Immunocytological and biochemical characterization of a new neuronal cell surface component (L1 antigen) which is involved in cell adhesion. EMBO J. 1984; 3:1–10. PubMed PMC

Chang S, Rathjen FG, Raper JA. Extension of neurites on axons is impaired by antibodies against specific neural cell surface glycoproteins. J Cell Biol. 1987; 104:355–62. 10.1083/jcb.104.2.355 PubMed DOI PMC

Fischer G, Künemund V, Schachner M. Neurite outgrowth patterns in cerebellar microexplant cultures are affected by antibodies to the cell surface glycoprotein L1. J Neurosci. 1986; 6:605–12. PubMed PMC

Keilhauer G, Faissner A, Schachner M. Differential inhibition of neurone-neurone, neurone-astrocyte and astrocyte-astrocyte adhesion by L1, L2 and N-CAM antibodies. Nature. 1985; 316:728–30. 10.1038/316728a0 PubMed DOI

Lindner J, Rathjen FG, Schachner M. L1 mono- and polyclonal antibodies modify cell migration in early postnatal mouse cerebellum. Nature. 1983; 305:427–30. 10.1038/305427a0 PubMed DOI

Bapat AA, Hostetter G, Von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer. 2011; 11:695–707. 10.1038/nrc3131 PubMed DOI

Geismann C, Arlt A, Bauer I, Pfeifer M, Schirmer U, Altevogt P, Müerköster SS, Schäfer H. Binding of the transcription factor Slug to the L1CAM promoter is essential for transforming growth factor-β1 (TGF-β)-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. Int J Oncol. 2011; 38:257–66. PubMed

Cheng L, Wu Q, Huang Z, Guryanova OA, Huang Q, Shou W, Rich JN, Bao S. L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J. 2011; 30:800–13. 10.1038/emboj.2011.10 PubMed DOI PMC

Nishimune H, Bernreuther C, Carroll P, Chen S, Schachner M, Henderson CE. Neural adhesion molecules L1 and CHL1 are survival factors for motoneurons. J Neurosci Res. 2005; 80:593–99. 10.1002/jnr.20517 PubMed DOI

Friedli A, Fischer E, Novak-Hofer I, Cohrs S, Ballmer-Hofer K, Schubiger PA, Schibli R, Grünberg J. The soluble form of the cancer-associated L1 cell adhesion molecule is a pro-angiogenic factor. Int J Biochem Cell Biol. 2009; 41:1572–80. 10.1016/j.biocel.2009.01.006 PubMed DOI

Mechtersheimer S, Gutwein P, Agmon-Levin N, Stoeck A, Oleszewski M, Riedle S, Postina R, Fahrenholz F, Fogel M, Lemmon V, Altevogt P. Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol. 2001; 155:661–73. 10.1083/jcb.200101099 PubMed DOI PMC

Sebens Müerköster S, Werbing V, Sipos B, Debus MA, Witt M, Grossmann M, Leisner D, Kötteritzsch J, Kappes H, Klöppel G, Altevogt P, Fölsch UR, Schäfer H. Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells. Oncogene. 2007; 26:2759–68. 10.1038/sj.onc.1210076 PubMed DOI

Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009; 19:128–39. 10.1038/cr.2008.328 PubMed DOI PMC

Kretzschmar M, Doody J, Timokhina I, Massagué J. A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev. 1999; 13:804–16. 10.1101/gad.13.7.804 PubMed DOI PMC

Battini R, Ferrari S, Kaczmarek L, Calabretta B, Chen ST, Baserga R. Molecular cloning of a cDNA for a human ADP/ATP carrier which is growth-regulated. J Biol Chem. 1987; 262:4355–59. PubMed

Luciakova K, Kollarovic G, Kretova M, Sabova L, Nelson BD. TGF-β signals the formation of a unique NF1/Smad4-dependent transcription repressor-complex in human diploid fibroblasts. Biochem Biophys Res Commun. 2011; 411:648–53. 10.1016/j.bbrc.2011.07.017 PubMed DOI

Schmid RS, Pruitt WM, Maness PF. A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis. J Neurosci. 2000; 20:4177–88. PubMed PMC

McRobb LS, McKay MJ, Gamble JR, Grace M, Moutrie V, Santos ED, Lee VS, Zhao Z, Molloy MP, Stoodley MA. Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence. Aging (Albany NY). 2017; 9:1248–68. 10.18632/aging.101225 PubMed DOI PMC

Cruickshanks HA, McBryan T, Nelson DM, Vanderkraats ND, Shah PP, van Tuyn J, Singh Rai T, Brock C, Donahue G, Dunican DS, Drotar ME, Meehan RR, Edwards JR, et al. Senescent cells harbour features of the cancer epigenome. Nat Cell Biol. 2013; 15:1495–506. 10.1038/ncb2879 PubMed DOI PMC

Harper KL, Sosa MS, Entenberg D, Hosseini H, Cheung JF, Nobre R, Avivar-Valderas A, Nagi C, Girnius N, Davis RJ, Farias EF, Condeelis J, Klein CA, Aguirre-Ghiso JA. Mechanism of early dissemination and metastasis in Her2+mammary cancer. Nature. 2016; 540:588–92. 10.1038/nature20609 PubMed DOI PMC

Hosseini H, Obradović MM, Hoffmann M, Harper KL, Sosa MS, Werner-Klein M, Nanduri LK, Werno C, Ehrl C, Maneck M, Patwary N, Haunschild G, Gužvić M, et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016; 540:552–58. 10.1038/nature20785 PubMed DOI PMC

Bernards R, Weinberg RA. A progression puzzle. Nature. 2002; 418:823. 10.1038/418823a PubMed DOI

Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003; 22:4212–22. 10.1093/emboj/cdg417 PubMed DOI PMC

Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell. 2008; 14:79–89. 10.1016/j.ccr.2008.06.005 PubMed DOI

Novakova Z, Hubackova S, Kosar M, Janderova-Rossmeislova L, Dobrovolna J, Vasicova P, Vancurova M, Horejsi Z, Hozak P, Bartek J, Hodny Z. Cytokine expression and signaling in drug-induced cellular senescence. Oncogene. 2010; 29:273–84. 10.1038/onc.2009.318 PubMed DOI

Kosar M, Bartkova J, Hubackova S, Hodny Z, Lukas J, Bartek J. Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). Cell Cycle. 2011; 10:457–68. 10.4161/cc.10.3.14707 PubMed DOI

Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995; 92:9363–67. 10.1073/pnas.92.20.9363 PubMed DOI PMC

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001; 25:402–08. 10.1006/meth.2001.1262 PubMed DOI

Maninová M, Klímová Z, Parsons JT, Weber MJ, Iwanicki MP, Vomastek T. The reorientation of cell nucleus promotes the establishment of front-rear polarity in migrating fibroblasts. J Mol Biol. 2013; 425:2039–55. 10.1016/j.jmb.2013.02.034 PubMed DOI

L1CAM Is Not a Predictive Factor in Early-stage Squamous-cell Cervical Cancer

Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs