Modelling aggressive prostate cancers of young men in immune-competent mice, driven by isogenic Trp53 alterations and Pten loss.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
08 09 2022
08 09 2022
Historique:
received:
26
05
2022
accepted:
23
08
2022
revised:
18
08
2022
entrez:
8
9
2022
pubmed:
9
9
2022
medline:
14
9
2022
Statut:
epublish
Résumé
Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including immunotherapies. Our prostate cancer models strongly support the role of tumour suppressor p53 in functioning to critically restrain the emergence of cancer pathways that drive cell cycle progression; alter metabolism and vasculature to fuel tumour growth; and mediate epithelial to mesenchymal-transition, as vital to invasion. Importantly, we also discovered that the type of p53 alteration dictates the specific immune cell profiles most significantly disrupted, in a temporal manner, with ramifications for disease progression. These new orthotopic mouse models demonstrate that each of the isogenic hotspot p53 amino acid mutations studied (R172H and R245W, the mouse equivalents of human R175H and R248W respectively), drive unique cellular changes affecting pathways of proliferation and immunity. Our findings support the hypothesis that individual p53 mutations confer their own particular oncogenic gain of function in prostate cancer.
Identifiants
pubmed: 36075907
doi: 10.1038/s41419-022-05211-y
pii: 10.1038/s41419-022-05211-y
pmc: PMC9465983
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
PTEN Phosphohydrolase
EC 3.1.3.67
PTEN protein, human
EC 3.1.3.67
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
777Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA082577
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
PLoS Biol. 2003 Dec;1(3):E59
pubmed: 14691534
Nat Genet. 2001 Dec;29(4):418-25
pubmed: 11694875
Cell Cycle. 2013 Jun 1;12(11):1722-31
pubmed: 23656786
J Vis Exp. 2018 Sep 18;(139):
pubmed: 30295668
Am J Clin Oncol. 2020 Apr;43(4):288-297
pubmed: 31972568
Genes Dev. 2000 Apr 15;14(8):994-1004
pubmed: 10783170
J Immunother Cancer. 2020 Jun;8(1):
pubmed: 32581061
Cancer Res. 2018 Aug 15;78(16):4671-4679
pubmed: 29921693
Cell. 2015 May 21;161(5):1215-1228
pubmed: 26000489
Cell Rep. 2019 Jul 30;28(5):1370-1384.e5
pubmed: 31365877
Int J Mol Med. 2018 Dec;42(6):3395-3403
pubmed: 30320350
BJU Int. 2015 Apr;115 Suppl 5:16-23
pubmed: 25124107
Am J Pathol. 2011 Jul;179(1):422-35
pubmed: 21703421
Front Oncol. 2020 Oct 23;10:587386
pubmed: 33194742
Nat Cell Biol. 2021 Jan;23(1):87-98
pubmed: 33420488
Nat Rev Urol. 2018 Apr;15(4):222-234
pubmed: 29460925
Asian J Urol. 2015 Jan;2(1):11-18
pubmed: 29051866
Transl Oncol. 2020 Jun;13(6):100773
pubmed: 32334405
Oncogene. 2022 Jan;41(3):444-458
pubmed: 34773073
Mol Oncol. 2013 Apr;7(2):190-205
pubmed: 23481269
J Clin Invest. 2019 Feb 1;129(2):452-464
pubmed: 30614812
Cold Spring Harb Perspect Med. 2020 Feb 3;10(2):
pubmed: 31570383
Nucleic Acids Res. 2015 Jan;43(Database issue):D805-11
pubmed: 25355519
World J Oncol. 2019 Apr;10(2):63-89
pubmed: 31068988
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12372-7
pubmed: 21746896
Genome Med. 2021 Apr 29;13(1):73
pubmed: 33926541
Science. 2021 Sep 17;373(6561):1327-1335
pubmed: 34529489
Science. 2017 Jan 6;355(6320):78-83
pubmed: 28059767
Lancet. 2021 Sep 18;398(10305):1075-1090
pubmed: 34370973
Mol Metab. 2020 Mar;33:2-22
pubmed: 31685430
Int J Mol Sci. 2021 Oct 12;22(20):
pubmed: 34681666
Nat Cell Biol. 2021 Jan;23(1):3-5
pubmed: 33420486
Nature. 2008 Oct 23;455(7216):1129-33
pubmed: 18948956
Cancer Res. 2004 Mar 15;64(6):2270-305
pubmed: 15026373
CA Cancer J Clin. 2020 Jan;70(1):7-30
pubmed: 31912902
Nat Rev Dis Primers. 2021 Feb 4;7(1):9
pubmed: 33542230
Sci Rep. 2017 Jun 14;7(1):3495
pubmed: 28615666
PLoS One. 2013;8(1):e53501
pubmed: 23308238
Immunity. 2020 Jan 14;52(1):17-35
pubmed: 31940268
J Biol Chem. 2011 Dec 2;286(48):41600-41615
pubmed: 21862591
Cell Death Differ. 2014 Sep;21(9):1419-31
pubmed: 24832469
Nat Commun. 2019 Dec 11;10(1):5649
pubmed: 31827082
Nat Commun. 2015 Apr 01;6:6605
pubmed: 25827447
Genes Dev. 2021 Apr 1;35(7-8):433-448
pubmed: 33861719
Clin Oncol (R Coll Radiol). 2006 Mar;18(2):109-16
pubmed: 16523810
Cell Death Dis. 2020 Apr 16;11(4):234
pubmed: 32300100
Nat Rev Clin Oncol. 2018 Apr;15(4):234-248
pubmed: 29405201
Radiat Environ Biophys. 2018 Aug;57(3):241-249
pubmed: 29850926
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Endocrinology. 2018 Jul 1;159(7):2596-2613
pubmed: 29767714
Nat Commun. 2018 Sep 27;9(1):3953
pubmed: 30262850
Oncotarget. 2017 Dec 5;8(67):111882-111901
pubmed: 29340098
Front Immunol. 2021 Oct 28;12:686809
pubmed: 34777331
Br J Cancer. 2020 Feb;122(3):405-412
pubmed: 31780779
BMC Cancer. 2021 Jul 26;21(1):856
pubmed: 34311724
Cancer. 2020 Jan 1;126(1):46-57
pubmed: 31553489
J Immunol. 2018 Mar 15;200(6):1982-1987
pubmed: 29440507
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Genesis. 2012 Nov;50(11):819-27
pubmed: 22644989
Nat Commun. 2013;4:2935
pubmed: 24343302
Science. 2019 Aug 9;365(6453):599-604
pubmed: 31395785
PLoS One. 2020 May 15;15(5):e0226057
pubmed: 32413024
Int J Mol Sci. 2021 Sep 02;22(17):
pubmed: 34502458
Cell Death Differ. 2018 Jan;25(1):154-160
pubmed: 29099487
Cancers (Basel). 2021 May 02;13(9):
pubmed: 34063238
J Pathol. 2017 Apr;241(5):661-670
pubmed: 28097652
Br J Cancer. 2019 Oct;121(7):578-583
pubmed: 31409910
Nat Rev Urol. 2014 Jun;11(6):317-23
pubmed: 24818853
PLoS One. 2020 Sep 28;15(9):e0232807
pubmed: 32986721
Int J Radiat Oncol Biol Phys. 2018 Jan 1;100(1):188-198
pubmed: 29102647
Cancers (Basel). 2020 Jul 02;12(7):
pubmed: 32630699
Cell. 2004 Dec 17;119(6):861-72
pubmed: 15607981
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15312-7
pubmed: 22949650
Br J Cancer. 2020 Jun;122(12):1732-1743
pubmed: 32327707
Asian Pac J Cancer Prev. 2015;16(13):5137-41
pubmed: 26225642
Cell Death Differ. 2019 Jan;26(2):199-212
pubmed: 30538286
J Mol Cell Biol. 2019 Jul 19;11(7):610-614
pubmed: 31282931
Sci Rep. 2021 Nov 18;11(1):22495
pubmed: 34795362
Genes Dev. 2017 Sep 15;31(18):1847-1857
pubmed: 29021240
Mech Dev. 2001 Mar;101(1-2):61-9
pubmed: 11231059
Nat Cell Biol. 2016 Aug;18(8):897-909
pubmed: 27347849
Int J Mol Sci. 2020 May 13;21(10):
pubmed: 32414156
Cell Signal. 2022 Mar;91:110221
pubmed: 34933092
Nat Rev Cancer. 2019 Mar;19(3):133-150
pubmed: 30755690
Cell. 2016 Oct 6;167(2):397-404.e9
pubmed: 27667683
Cell Death Dis. 2017 Mar 9;8(3):e2661
pubmed: 28277540
Sci Rep. 2016 Sep 23;6:34019
pubmed: 27659694
Cancers (Basel). 2020 Jun 11;12(6):
pubmed: 32545367
Nat Genet. 2009 May;41(5):544-52
pubmed: 19282848