Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells

Abstract

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.Nat Genet. 2014 May;46(5):444-450. (PMID: 24705251); Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16910-5. (PMID: 20837533); Nature. 2011 Jan 20;469(7330):356-61. (PMID: 21160474); Acta Neuropathol Commun. 2016 Jan 04;4:1. (PMID: 26727948); Cancer Cell. 2017 Oct 9;32(4):520-537.e5. (PMID: 28966033); Nat Rev Clin Oncol. 2012 May 29;9(7):400-13. (PMID: 22641364); Cell Rep. 2014 Jun 26;7(6):2006-18. (PMID: 24931610); Science. 2014 Oct 10;346(6206):251-6. (PMID: 25301630); Nat Genet. 2014 May;46(5):457-461. (PMID: 24705252); Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4453-8. (PMID: 21368213); Cancer Discov. 2011 Aug;1(3):260-73. (PMID: 21984977); Cancer Cell. 2015 Jan 12;27(1):15-26. (PMID: 25584892); Nature. 2014 Oct 2;514(7520):54-8. (PMID: 25079331); Oncogene. 2013 Nov 21;32(47):5377-87. (PMID: 23934192); J Clin Oncol. 2016 Jul 1;34(19):2206-11. (PMID: 27001570); Nat Commun. 2016 Apr 06;7:11185. (PMID: 27048880); Nat Rev Cancer. 2014 Feb;14(2):92-107. (PMID: 24457416); N Engl J Med. 2012 Mar 8;366(10):883-892. (PMID: 22397650); Nat Med. 2016 Jan;22(1):105-13. (PMID: 26618723); Acta Neuropathol Commun. 2017 Oct 30;5(1):78. (PMID: 29084603); Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3041-6. (PMID: 22323597); Acta Neuropathol. 2014 Oct;128(4):605-7. (PMID: 24929912); Cancer Res. 2012 Apr 1;72(7):1614-20. (PMID: 22311673); Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):851-6. (PMID: 25561528); J Clin Oncol. 2011 Oct 20;29(30):3999-4006. (PMID: 21931021); Nat Commun. 2014 Jun 09;5:4091. (PMID: 24909977); Nat Genet. 2012 Jan 29;44(3):251-3. (PMID: 22286216); Cell Stem Cell. 2009 Jun 5;4(6):568-80. (PMID: 19497285); Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4009-14. (PMID: 23412337); Nat Genet. 2014 May;46(5):451-6. (PMID: 24705254); Science. 2014 Jun 20;344(6190):1396-401. (PMID: 24925914); BMC Biol. 2012 Mar 22;10:29. (PMID: 22439642); Nat Med. 2016 Nov;22(11):1314-1320. (PMID: 27748748); J Vis Exp. 2015 May 01;(99):e52686. (PMID: 25993495); Nat Rev Cancer. 2014 Oct;14(10):. (PMID: 25230881); Neuro Oncol. 2015 Aug;17(8):1051-63. (PMID: 25934816); Clin Cancer Res. 2015 Mar 15;21(6):1258-66. (PMID: 25770293); Nat Commun. 2014;5:2997. (PMID: 24429703); PLoS One. 2012;7(2):e30313. (PMID: 22389665); Nucleic Acids Res. 2013 Mar 1;41(5):2797-806. (PMID: 23345616); Nat Med. 2014 Dec;20(12):1394-6. (PMID: 25401693); Science. 2006 Dec 8;314(5805):1560-3. (PMID: 17158317); Hum Mol Genet. 2013 Jan 1;22(1):84-95. (PMID: 23035050); Nat Genet. 2014 May;46(5):462-6. (PMID: 24705250); Science. 2014 Dec 19;346(6216):1529-33. (PMID: 25525250); Nat Genet. 2017 May;49(5):780-788. (PMID: 28394352); Methods Mol Biol. 2013;986:253-66. (PMID: 23436417); Acta Neuropathol. 2015 Dec;130(6):815-27. (PMID: 26399631); Cell Stem Cell. 2014 Mar 6;14(3):275-91. (PMID: 24607403); Nature. 2012 Jan 29;482(7384):226-31. (PMID: 22286061); Cell Rep. 2014 Aug 7;8(3):688-95. (PMID: 25066122); Bioinformatics. 2014 Jan 1;30(1):50-60. (PMID: 24177718); J Clin Oncol. 2015 Sep 20;33(27):2986-98. (PMID: 26304884); Nat Med. 2015 Jun;21(6):555-9. (PMID: 25939062); Science. 2014 Jan 10;343(6167):189-193. (PMID: 24336570); Nature. 2012 Jan 11;481(7382):506-10. (PMID: 22237025). Linking ISSN: 10788956. Subset: MEDLINE; Grant Information: 13982 United Kingdom CRUK_ Cancer Research UK; A13982 United Kingdom CRUK_ Cancer Research UK; A23536 United Kingdom CRUK_ Cancer Research UK; K08 NS070926 United States NS NINDS NIH HHS Date of Electronic Publication: 2018 Jul 02. Current Imprints: Publication: New York Ny : Nature Publishing Company Original Imprints: Publication: New York, NY : Nature Pub. Co., [1995- <br />