Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
28
08
2021
accepted:
16
06
2022
pubmed:
29
7
2022
medline:
10
8
2022
entrez:
28
7
2022
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.
Identifiants
pubmed: 35902743
doi: 10.1038/s41588-022-01134-8
pii: 10.1038/s41588-022-01134-8
pmc: PMC10290535
mid: NIHMS1901221
doi:
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1178-1191Subventions
Organisme : NCI NIH HHS
ID : K08 CA270417
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA224348
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
J Clin Oncol. 2022 Apr 10;40(11):1220-1230
pubmed: 35084987
Nat Commun. 2021 Nov 25;12(1):6876
pubmed: 34824236
Cancer Cell. 2016 Oct 10;30(4):563-577
pubmed: 27728805
Br J Cancer. 2012 Mar 13;106(6):1033-8
pubmed: 22374460
Stem Cell Res. 2019 May;37:101430
pubmed: 30933720
Nat Med. 2021 Mar;27(3):546-559
pubmed: 33654293
Cell. 2021 Oct 28;184(22):5577-5592.e18
pubmed: 34644529
Elife. 2019 Jul 08;8:
pubmed: 31282856
Cell Death Dis. 2015 Feb 19;6:e1647
pubmed: 25695600
Clin Pharmacokinet. 2018 Oct;57(10):1229-1254
pubmed: 29520731
Nat Rev Gastroenterol Hepatol. 2019 Apr;16(4):207-220
pubmed: 30718832
Cell. 2016 Jul 14;166(2):328-342
pubmed: 27374332
Int J Gynecol Cancer. 2018 Feb;28(2):323-331
pubmed: 29240605
Clin Cancer Res. 2021 Jul 15;27(14):3825-3833
pubmed: 33653818
Development. 2015 Apr 15;142(8):1516-27
pubmed: 25813538
J Hepatol. 2018 May;68(5):1033-1048
pubmed: 29175243
Sci Rep. 2019 Aug 2;9(1):11239
pubmed: 31375762
Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28960-28970
pubmed: 33127761
Lancet Oncol. 2022 Feb;23(2):e62-e74
pubmed: 35114133
Neuron. 2018 Mar 7;97(5):1049-1062.e6
pubmed: 29429939
Cancer Discov. 2021 Aug;11(8):2014-2031
pubmed: 33727309
Cancer Chemother Pharmacol. 2019 Apr;83(4):603-613
pubmed: 30627777
Cell. 2020 Sep 17;182(6):1606-1622.e23
pubmed: 32888429
Nat Commun. 2017 Nov 23;8(1):1728
pubmed: 29170413
Nat Genet. 2020 Feb;52(2):231-240
pubmed: 31932696
Nat Med. 2020 May;26(5):792-802
pubmed: 32405060
Genome Biol. 2018 Feb 6;19(1):15
pubmed: 29409532
Cancer Discov. 2019 Aug;9(8):1102-1123
pubmed: 31197017
Nat Methods. 2019 Dec;16(12):1226-1232
pubmed: 31570887
J Biol Chem. 2017 Jan 27;292(4):1330-1338
pubmed: 27994051
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18907-12
pubmed: 19028876
Gastroenterology. 2021 Mar;160(4):1330-1344.e11
pubmed: 33212097
Nat Med. 2015 Aug;21(8):938-945
pubmed: 26193342
Nat Methods. 2019 Dec;16(12):1289-1296
pubmed: 31740819
Oncotarget. 2016 Nov 22;7(47):77838-77853
pubmed: 27788482
Pharmacol Ther. 2017 Nov;179:158-170
pubmed: 28549596
Nature. 2016 Mar 3;531(7592):47-52
pubmed: 26909576
Br J Cancer. 2021 Jul;125(2):149-151
pubmed: 33772153
Lancet. 2020 Jun 27;395(10242):2008-2020
pubmed: 32593337
Neuron. 2007 Dec 6;56(5):807-22
pubmed: 18054858
Cell. 2015 Jan 15;160(1-2):324-38
pubmed: 25557080
Adv Cancer Res. 2018;137:37-75
pubmed: 29405977
Front Mol Neurosci. 2018 Nov 20;11:422
pubmed: 30515076
Clin Cancer Res. 2021 May 15;27(10):2807-2815
pubmed: 33632928
Cancer Cell. 2007 Mar;11(3):291-302
pubmed: 17349585
Clin Cancer Res. 2017 Oct 1;23(19):5959-5969
pubmed: 28600474
Nucleic Acids Res. 2019 Jun 4;47(10):5325-5340
pubmed: 30937446
JAMA Oncol. 2019 Jul 01;5(7):1020-1027
pubmed: 31145418
Nat Rev Gastroenterol Hepatol. 2020 Aug;17(8):487-505
pubmed: 32393771
Clin Cancer Res. 2019 Apr 1;25(7):2194-2205
pubmed: 30385653
Science. 2014 Jun 20;344(6190):1396-401
pubmed: 24925914
Dev Cell. 2018 Jun 18;45(6):681-695.e4
pubmed: 29920274
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
J Biol Chem. 2015 May 22;290(21):13567-77
pubmed: 25851906
Front Immunol. 2017 Jan 17;8:15
pubmed: 28144242
PLoS Biol. 2018 Jul 3;16(7):e2005970
pubmed: 29969450
J Clin Invest. 2010 Feb;120(2):508-20
pubmed: 20071774
J Immunol. 2020 Oct 15;205(8):2169-2187
pubmed: 32948687
Brain Sci. 2017 May 14;7(5):
pubmed: 28505103
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Genomics. 2000 Dec 1;70(2):264-8
pubmed: 11112355
Clin Cancer Res. 2018 Mar 15;24(6):1344-1354
pubmed: 29288237
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Nat Biotechnol. 2020 May;38(5):586-599
pubmed: 32393914
Int J Dev Biol. 2009;53(1):81-9
pubmed: 19123129
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Commun. 2019 Mar 20;10(1):1295
pubmed: 30894541
Nat Methods. 2017 Oct;14(10):955-958
pubmed: 28846088
Cell. 2017 Oct 19;171(3):540-556.e25
pubmed: 28988769
Cancer Lett. 2015 Jun 28;362(1):45-60
pubmed: 25779676
Nature. 2006 Jul 20;442(7100):299-302
pubmed: 16855590
Nat Biotechnol. 2020 Mar;38(3):333-342
pubmed: 31932730
Nat Med. 2011 Apr;17(4):500-3
pubmed: 21460848
Cell. 2019 Jun 27;178(1):160-175.e27
pubmed: 31155233
Gastroenterology. 2020 Aug;159(2):665-681.e13
pubmed: 32330476
Cell Res. 2019 Sep;29(9):725-738
pubmed: 31273297
Nat Commun. 2020 Feb 21;11(1):1009
pubmed: 32081882
BMC Bioinformatics. 2013 Jan 16;14:7
pubmed: 23323831
Cell Syst. 2016 Oct 26;3(4):385-394.e3
pubmed: 27693023
Cancer Cell. 2017 Aug 14;32(2):185-203.e13
pubmed: 28810144
Sci Rep. 2019 Mar 26;9(1):5233
pubmed: 30914743
Nature. 2016 Sep 15;537(7620):417-421
pubmed: 27501248
Development. 2019 Jul 15;146(14):
pubmed: 31235634
Nature. 2021 May;593(7860):575-579
pubmed: 33981032
Nature. 2012 Nov 15;491(7424):399-405
pubmed: 23103869
Circulation. 2021 Jul 27;144(4):286-302
pubmed: 34030460
Cell. 2017 Dec 14;171(7):1611-1624.e24
pubmed: 29198524
Genome Biol. 2019 Mar 19;20(1):59
pubmed: 30890159
Oncotarget. 2015 May 10;6(13):10853-67
pubmed: 25890497
Nat Cancer. 2020 Nov;1(11):1097-1112
pubmed: 34296197
Neuron. 2004 Dec 16;44(6):961-75
pubmed: 15603739
Cancer Cell. 2021 Oct 11;39(10):1342-1360.e14
pubmed: 34358448
J Invest Dermatol. 1991 Jul;97(1):97-100
pubmed: 2056197
Cell. 2021 Dec 9;184(25):6119-6137.e26
pubmed: 34890551
J Vis Exp. 2014 Aug 02;(90):e51779
pubmed: 25145327
J Allergy Clin Immunol. 2018 Oct;142(4):1257-1271.e4
pubmed: 29391257
N Engl J Med. 2018 Dec 20;379(25):2395-2406
pubmed: 30575490
Mol Cell Neurosci. 2012 Mar;49(3):351-63
pubmed: 22182708
Cancer Cell. 2014 Dec 8;26(6):923-937
pubmed: 25465800
Nat Commun. 2016 Feb 29;7:10798
pubmed: 26924072
Sci Rep. 2018 Jan 10;8(1):256
pubmed: 29321503
Clin Cancer Res. 2021 Feb 15;27(4):1069-1081
pubmed: 33262135
Science. 2020 Mar 6;367(6482):
pubmed: 32139519
FASEB J. 2020 Sep;34(9):12214-12228
pubmed: 32686876
Immunity. 2019 May 21;50(5):1317-1334.e10
pubmed: 30979687
J Cell Biochem. 2002;87(1):1-8
pubmed: 12210716
Nat Methods. 2017 Sep;14(9):873-876
pubmed: 28783155