title: Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.
abstract: Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.
  
  
  CONCLUSIONS
  Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2.
authors.affiliation: 1Abramson Family Cancer Research Institute; 2Perelman School of Medicine, University of Pennsylvania; 3The Wistar Institute, Philadelphia, Pennsylvania; Departments of 4Pharmacology and Cancer Biology and 5Radiation Oncology, Duke University Medical Center, Durham, North Carolina; 6Howard Hughes Medical Institute; 7Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; and 8Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: T S Karin
authors.initials: TS
authors.lastname: Eisinger-Mathason
authors.forename: Minsi
authors.initials: M
authors.lastname: Zhang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Qiu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.forename: Michael S
authors.initials: MS
authors.lastname: Nakazawa
authors.forename: Tatiana
authors.initials: T
authors.lastname: Karakasheva
authors.forename: Vera
authors.initials: V
authors.lastname: Mucaj
authors.forename: Jessica E S
authors.initials: JE
authors.lastname: Shay
authors.forename: Lars
authors.initials: L
authors.lastname: Stangenberg
authors.forename: Navid
authors.initials: N
authors.lastname: Sadri
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Sam S
authors.initials: SS
authors.lastname: Yoon
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008914:Minoxidil / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D012513:Sarcoma, Experimental / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008914:Minoxidil; D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
references.citation: J Biol Chem. 2007 Nov 16;282(46):33381-33388
references.pmid: 17873278
references.citation: Nat Med. 2007 Aug;13(8):992-7
references.pmid: 17676052
references.citation: Nat Rev Cancer. 2006 May;6(5):392-401
references.pmid: 16572188
references.citation: Expert Rev Anticancer Ther. 2009 Aug;9(8):1135-44
references.pmid: 19671033
references.citation: J Biol Chem. 2013 Apr 12;288(15):10819-29
references.pmid: 23423382
references.citation: Cancer. 2011 Mar 1;117(5):1049-54
references.pmid: 20945333
references.citation: Cancer Cell. 2010 Apr 13;17(4):319-32
references.pmid: 20385358
references.citation: Matrix Biol. 2005 Jun;24(4):261-70
references.pmid: 15908192
references.citation: J Mol Med (Berl). 2012 Jul;90(7):803-15
references.pmid: 22231744
references.citation: Cancer Res. 1996 Mar 1;56(5):941-3
references.pmid: 8640781
references.citation: Trends Genet. 2004 Jan;20(1):33-43
references.pmid: 14698617
references.citation: Cell. 2009 Nov 25;139(5):891-906
references.pmid: 19931152
references.citation: Nat Rev Cancer. 2003 Sep;3(9):685-94
references.pmid: 12951587
references.citation: Cancer Res. 2000 Aug 1;60(15):4010-5
references.pmid: 10945599
references.citation: PLoS One. 2009 Nov 30;4(11):e8075
references.pmid: 19956606
references.citation: Cancer Res. 2002 Nov 1;62(21):6278-88
references.pmid: 12414658
references.citation: Br J Cancer. 2001 Apr 20;84(8):1070-5
references.pmid: 11308256
references.citation: Cancer Res. 2006 Mar 1;66(5):2725-31
references.pmid: 16510593
references.citation: Cancer Res. 2010 Jun 1;70(11):4366-74
references.pmid: 20460529
references.citation: Int J Cancer. 2013 Jan 1;132(1):29-41
references.pmid: 22684860
references.citation: Cancer Cell. 2011 Feb 15;19(2):157-9
references.pmid: 21316595
references.citation: Biochemistry. 1981 Dec 22;20(26):7409-15
references.pmid: 6798991
references.citation: Nat Rev Cancer. 2011 Jul 14;11(8):541-57
references.pmid: 21753790
references.citation: Cancer Cell. 2012 Mar 20;21(3):309-22
references.pmid: 22439926
references.citation: Oncogene. 2012 Apr 5;31(14):1757-70
references.pmid: 21860410
references.citation: Cancer Res. 2006 Nov 1;66(21):10238-41
references.pmid: 17079439
references.citation: J Biol Chem. 2002 Jun 21;277(25):23084-91
references.pmid: 11956192
references.citation: Nat Rev Cancer. 2011 Jul 22;11(8):573-87
references.pmid: 21779009
references.citation: Curr Opin Cell Biol. 2010 Oct;22(5):697-706
references.pmid: 20822891
references.citation: Nat Rev Cancer. 2009 Apr;9(4):274-84
references.pmid: 19308067
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Cancer Cell. 2011 Feb 15;19(2):177-91
references.pmid: 21316601
references.citation: Nature. 2006 Apr 27;440(7088):1222-6
references.pmid: 16642001
references.citation: Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1207-16
references.pmid: 19545786
references.citation: Eur J Biochem. 2003 Nov;270(22):4515-22
references.pmid: 14622280
references.citation: Liver Int. 2012 Jan;32(1):110-8
references.pmid: 22098155
references.citation: J Biol Chem. 2010 Jul 16;285(29):22276-81
references.pmid: 20463013
references.citation: Cell Cycle. 2008 Jul 15;7(14):2090-6
references.pmid: 18635960
references.citation: Hum Mol Genet. 2013 Jan 1;22(1):1-17
references.pmid: 22949511
references.citation: Nat Rev Cancer. 2003 Dec;3(12):921-30
references.pmid: 14737122
references.citation: Nat Cell Biol. 2008 Mar;10(3):295-305
references.pmid: 18297062
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10889-94
references.pmid: 16832052
references.citation: J Biol Chem. 1996 Apr 19;271(16):9398-402
references.pmid: 8621606
references.citation: J Cell Biol. 2012 Feb 20;196(4):395-406
references.pmid: 22351925
references.citation: Cancer Res. 2005 Jul 1;65(13):5881-9
references.pmid: 15994966
references.citation: J Biol Chem. 2009 Nov 6;284(45):30917-24
references.pmid: 19762917
references.citation: Natl J Maxillofac Surg. 2012 Jan;3(1):15-20
references.pmid: 23251052