title: Regulated lysosomal exocytosis mediates cancer progression.
abstract: Understanding how tumor cells transition to an invasive and drug-resistant phenotype is central to cancer biology, but the mechanisms underlying this transition remain unclear. We show that sarcomas gain these malignant traits by inducing lysosomal exocytosis, a ubiquitous physiological process. During lysosomal exocytosis, the movement of exocytic lysosomes along the cytoskeleton and their docking at the plasma membrane involve LAMP1, a sialylated membrane glycoprotein and target of the sialidase NEU1. Cleavage of LAMP1 sialic acids by NEU1 limits the extent of lysosomal exocytosis. We found that by down-regulation of NEU1 and accumulation of oversialylated LAMP1, tumor cells exacerbate lysosomal exocytosis of soluble hydrolases and exosomes. This facilitates matrix invasion and propagation of invasive signals, and purging of lysosomotropic chemotherapeutics. In Arf (-⁄-) mice, Neu1 haploinsufficiency fostered the development of invasive, pleomorphic sarcomas, expressing epithelial and mesenchymal markers, and lysosomal exocytosis effectors, LAMP1 and Myosin-11. These features are analogous to those of metastatic, pleomorphic human sarcomas, where low NEU1 levels correlate with high expression of lysosomal exocytosis markers. In a therapeutic proof of principle, we demonstrate that inhibiting lysosomal exocytosis reversed invasiveness and chemoresistance in aggressive sarcoma cells. Thus, we reveal that this unconventional, lysosome-regulated pathway plays a primary role in tumor progression and chemoresistance.
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Eda
authors.initials: E
authors.lastname: Machado
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Shai
authors.initials: S
authors.lastname: White-Gilbertson
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Diantha
authors.initials: D
authors.lastname: van de Vlekkert
authors.affiliation: Department of Veterinary Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Janke
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Moshiach
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Campos
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Elida
authors.initials: E
authors.lastname: Gomero
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Rosario
authors.initials: R
authors.lastname: Mosca
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Ida
authors.initials: I
authors.lastname: Annunziata
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
keywords: Cancer progression; LAMP1; NEU1; intracellular trafficking; lysosomal exocytosis; lysosomes; sarcomas
references.citation: Cancer Res. 2011 Dec 15;71(24):7471-80
references.pmid: 22037868
references.citation: Science. 2014 Jan 17;343(6168):309-13
references.pmid: 24436421
references.citation: J Cell Biol. 1981 Apr;89(1):141-5
references.pmid: 7014571
references.citation: J Cell Biol. 1997 Apr 7;137(1):93-104
references.pmid: 9105039
references.citation: Glycoconj J. 2012 Dec;29(8-9):567-77
references.pmid: 22644327
references.citation: Cell. 2012 Dec 21;151(7):1542-56
references.pmid: 23260141
references.citation: Trends Mol Med. 2014 Jul;20(7):385-93
references.pmid: 24703619
references.citation: Cancer Sci. 2009 Sep;100(9):1573-80
references.pmid: 19555393
references.citation: Proteomics. 2008 Aug;8(16):3303-11
references.pmid: 18651674
references.citation: Biologics. 2014 Mar 17;8:91-105
references.pmid: 24669185
references.citation: J Biol Chem. 2013 Nov 1;288(44):31761-71
references.pmid: 24062304
references.citation: EMBO J. 1999 Apr 1;18(7):1772-82
references.pmid: 10202141
references.citation: Mod Pathol. 2000 Nov;13(11):1211-8
references.pmid: 11106079
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D1241-4
references.pmid: 21989406
references.citation: Cancer Cell. 2002 Dec;2(6):497-505
references.pmid: 12498718
references.citation: J Cell Sci. 1994 Jan;107 ( Pt 1):159-73
references.pmid: 8175905
references.citation: J Clin Invest. 2009 Jun;119(6):1420-8
references.pmid: 19487818
references.citation: Methods Mol Biol. 2010;596:341-58
references.pmid: 19949931
references.citation: Curr Opin Oncol. 2013 Jul;25(4):384-9
references.pmid: 23635801
references.citation: Virchows Arch. 2010 Feb;456(2):201-17
references.pmid: 20217954
references.citation: Cancer Res. 1999 May 1;59(9):2217-22
references.pmid: 10232611
references.citation: Curr Protoc Pharmacol. 2007 Dec;Chapter 14:Unit14.8
references.pmid: 21948167
references.citation: Nature. 2009 Jun 18;459(7249):1005-9
references.pmid: 19421193
references.citation: Pathol Int. 2006 Jun;56(6):287-95
references.pmid: 16704491
references.citation: J Cell Sci. 2014 Apr 15;127(Pt 8):1631-9
references.pmid: 24554434
references.citation: Am J Surg Pathol. 2001 Aug;25(8):1030-8
references.pmid: 11474287
references.citation: Mol Genet Metab. 2005 Jul;85(3):181-9
references.pmid: 15979029
references.citation: Hum Pathol. 2010 May;41(5):663-71
references.pmid: 20004935
references.citation: Dev Cell. 2008 Jul;15(1):74-86
references.pmid: 18606142
references.citation: Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):659-72
references.pmid: 20388541
references.citation: Microsc Res Tech. 2000 Sep 15;50(6):532-40
references.pmid: 10998642
references.citation: Nat Commun. 2013;4:2734
references.pmid: 24225533
references.citation: Oncogene. 2009 Mar 5;28(9):1218-29
references.pmid: 19151752
references.citation: Br J Cancer. 2000 Aug;83(3):338-45
references.pmid: 10917549
references.citation: Neurol Sci. 2011 Aug;32(4):737-8
references.pmid: 20706754
references.citation: Adv Carbohydr Chem Biochem. 2010;64:403-79
references.pmid: 20837202
references.citation: Pediatr Blood Cancer. 2007 Dec;49(7):928-40
references.pmid: 17066459
references.citation: Nat Rev Mol Cell Biol. 2002 Feb;3(2):122-31
references.pmid: 11836514
references.citation: Nat Rev Mol Cell Biol. 2009 Sep;10(9):623-35
references.pmid: 19672277
references.citation: Cell. 2001 Jul 27;106(2):157-69
references.pmid: 11511344
references.citation: Glycobiology. 2012 Jul;22(7):880-96
references.pmid: 22377912
references.citation: Nat Rev Cancer. 2009 Apr;9(4):274-84
references.pmid: 19308067
references.citation: Biochim Biophys Acta. 2010 Feb;1802(2):259-68
references.pmid: 19857571
references.citation: Bioessays. 2013 Jun;35(6):523-32
references.pmid: 23605698
references.citation: Biochem Pharmacol. 1999 May 1;57(9):1047-58
references.pmid: 10796075
references.citation: Int J Cancer. 2010 Jan 1;126(1):53-64
references.pmid: 19521958
references.citation: Mol Ther. 2002 Mar;5(3):242-51
references.pmid: 11863413
references.citation: Int J Cancer. 2005 Feb 20;113(5):752-60
references.pmid: 15499615
references.citation: J Clin Invest. 2014 Mar;124(3):1069-82
references.pmid: 24487586
references.citation: Clin Dev Immunol. 2011;2011:842849
references.pmid: 22190973
references.citation: Acta Neuropathol. 2010 Jan;119(1):135-45
references.pmid: 19415310
references.citation: Nat Med. 2010 Jul;16(7):781-7
references.pmid: 20581836
references.citation: Cancer Res. 2008 Jan 15;68(2):388-94
references.pmid: 18199532
references.citation: Proteomics. 2014 Mar;14(4-5):525-46
references.pmid: 24339177
references.citation: FASEB J. 2004 Jun;18(9):971-3
references.pmid: 15084520
references.citation: J Natl Cancer Inst. 2010 Jun 16;102(12 ):866-80
references.pmid: 20484105
references.citation: Cell Microbiol. 2000 Dec;2(6):477-86
references.pmid: 11207602
references.citation: Semin Cancer Biol. 2011 Apr;21(2):139-46
references.pmid: 21251983
references.citation: J Extracell Vesicles. 2012 Apr 16;1:null
references.pmid: 24009883