Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
04 Jan 2024
04 Jan 2024
Historique:
received:
22
03
2022
accepted:
10
11
2023
medline:
5
1
2024
pubmed:
5
1
2024
entrez:
4
1
2024
Statut:
aheadofprint
Résumé
Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.
Identifiants
pubmed: 38177458
doi: 10.1038/s43018-023-00686-w
pii: 10.1038/s43018-023-00686-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. https://doi.org/10.3322/caac.21660 (2021).
doi: 10.3322/caac.21660
pubmed: 33538338
Ajani, J. A. et al. Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology. J. Natl Compr. Canc. Netw. 14, 1286–1312 (2016).
pubmed: 27697982
doi: 10.6004/jnccn.2016.0137
Smyth, E. C., Nilsson, M., Grabsch, H. I., van Grieken, N. C. & Lordick, F. Gastric cancer. Lancet 396, 635–648 (2020).
pubmed: 32861308
doi: 10.1016/S0140-6736(20)31288-5
Wagner, A. D. et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 8, CD004064 (2017).
pubmed: 28850174
Huang, K. K. et al. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell 33, 137–150 (2018).
pubmed: 29290541
doi: 10.1016/j.ccell.2017.11.018
Cristescu, R. et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat. Med. 21, 449–456 (2015).
pubmed: 25894828
doi: 10.1038/nm.3850
Wang, K. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46, 573–582 (2014).
pubmed: 24816253
doi: 10.1038/ng.2983
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
doi: 10.1038/nature13480
Lauren, P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand. 64, 31–49 (1965).
pubmed: 14320675
doi: 10.1111/apm.1965.64.1.31
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
pubmed: 28596308
pmcid: 5576142
doi: 10.1126/science.aan6733
Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017).
pubmed: 29186113
doi: 10.1038/nature24673
Chao, J. et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2021.0275 (2021).
doi: 10.1001/jamaoncol.2021.0275
pubmed: 34591080
pmcid: 8485211
Kwon, M. et al. Determinants of response and intrinsic resistance to PD-1 blockade in microsatellite instability-high gastric cancer. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-21-0219 (2021).
doi: 10.1158/2159-8290.CD-21-0219
pubmed: 33846173
Kim, S. T. et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat. Med. 24, 1449–1458 (2018).
pubmed: 30013197
doi: 10.1038/s41591-018-0101-z
Till, J. E. et al. Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression. Cancer Res. 77, 5349–5359 (2017).
pubmed: 28760854
pmcid: 5626624
doi: 10.1158/0008-5472.CAN-17-0061
Seidlitz, T. et al. Mouse models of human gastric cancer subtypes with stomach-specific CreERT2-mediated pathway alterations. Gastroenterology 157, 1599–1614 (2019).
pubmed: 31585123
doi: 10.1053/j.gastro.2019.09.026
Fatehullah, A. et al. A tumour-resident Lgr5(+) stem-cell-like pool drives the establishment and progression of advanced gastric cancers. Nat. Cell Biol. 23, 1299–1313 (2021).
pubmed: 34857912
doi: 10.1038/s41556-021-00793-9
Hayakawa, Y. et al. Mouse models of gastric cancer. Cancers 5, 92–130 (2013).
pubmed: 24216700
pmcid: 3730302
doi: 10.3390/cancers5010092
Leibold, J. et al. Somatic tissue engineering in mouse models reveals an actionable role for WNT pathway alterations in prostate cancer metastasis. Cancer Discov. 10, 1038–1057 (2020).
pubmed: 32376773
pmcid: 7334089
doi: 10.1158/2159-8290.CD-19-1242
Seehawer, M. et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562, 69–75 (2018).
pubmed: 30209397
pmcid: 8111790
doi: 10.1038/s41586-018-0519-y
Paffenholz, S. V. et al. Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2117754119 (2022).
Maresch, R. et al. Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. Nat. Commun. 7, 10770 (2016).
pubmed: 26916719
pmcid: 4773438
doi: 10.1038/ncomms10770
Ding, L. et al. Perspective on oncogenic processes at the end of the beginning of cancer genomics. Cell 173, 305–320.e10 (2018).
Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003).
pubmed: 14522256
doi: 10.1016/S1535-6108(03)00197-1
Gaudelli, N. M. et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).
pubmed: 29160308
pmcid: 5726555
doi: 10.1038/nature24644
Syder, A. J. et al. A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype. Proc. Natl Acad. Sci. USA 101, 4471–4476 (2004).
pubmed: 15070742
pmcid: 384771
doi: 10.1073/pnas.0307983101
Mimata, A., Fukamachi, H., Eishi, Y. & Yuasa, Y. Loss of E-cadherin in mouse gastric epithelial cells induces signet ring-like cells, a possible precursor lesion of diffuse gastric cancer. Cancer Sci. 102, 942–950 (2011).
pubmed: 21276134
doi: 10.1111/j.1349-7006.2011.01890.x
Shimada, S. et al. Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer. Gut 61, 344–353 (2012).
pubmed: 21865403
doi: 10.1136/gutjnl-2011-300050
Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).
pubmed: 9872311
doi: 10.1038/25292
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
pubmed: 23945592
pmcid: 3776390
doi: 10.1038/nature12477
Andre, T. et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med. 383, 2207–2218 (2020).
pubmed: 33264544
doi: 10.1056/NEJMoa2017699
Westcott, P. M. K. et al. Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity. Nat. Genet. 55, 1686–1695 (2023).
Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 (2017).
pubmed: 28803728
pmcid: 5591072
doi: 10.1016/j.cell.2017.07.024
Ciriello, G. et al. Emerging landscape of oncogenic signatures across human cancers. Nat. Genet. 45, 1127–1133 (2013).
pubmed: 24071851
pmcid: 4320046
doi: 10.1038/ng.2762
Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).
pubmed: 23562644
pmcid: 3702034
doi: 10.1016/j.cell.2013.03.020
Powell, E., Piwnica-Worms, D. & Piwnica-Worms, H. Contribution of p53 to metastasis. Cancer Discov. 4, 405–414 (2014).
pubmed: 24658082
pmcid: 4063123
doi: 10.1158/2159-8290.CD-13-0136
Iotsova, V. & Stehelin, D. Down-regulation of fibronectin gene expression by the p53 tumor suppressor protein. Cell Growth Differ. 7, 629–634 (1996).
pubmed: 8732672
Habano, W., Nakamura, S. & Sugai, T. Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome. Oncogene 17, 1931–1937 (1998).
pubmed: 9788436
doi: 10.1038/sj.onc.1202112
Rashid, S. et al. MLH1 deficiency leads to deregulated mitochondrial metabolism. Cell Death Dis. 10, 795 (2019).
pubmed: 31641109
pmcid: 6805956
doi: 10.1038/s41419-019-2018-y
Chen, B., Khodadoust, M. S., Liu, C. L., Newman, A. M. & Alizadeh, A. A. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol. Biol. 1711, 243–259 (2018).
pubmed: 29344893
pmcid: 5895181
doi: 10.1007/978-1-4939-7493-1_12
Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).
pubmed: 28481359
pmcid: 5461196
doi: 10.1038/nm.4333
Nguyen, B. et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 185, 563–575 (2022).
pubmed: 35120664
pmcid: 9147702
doi: 10.1016/j.cell.2022.01.003
Gilliland, R. & Gill, P. J. Incidence and prognosis of Krukenberg tumour in Northern Ireland. Br. J. Surg. 79, 1364–1366 (1992).
pubmed: 1336701
doi: 10.1002/bjs.1800791241
Yakushiji, M., Tazaki, T., Nishimura, H. & Kato, T. Krukenberg tumors of the ovary: a clinicopathologic analysis of 112 cases. Nihon Sanka Fujinka Gakkai Zasshi 39, 479–485 (1987).
pubmed: 3031182
Al-Agha, O. M. & Nicastri, A. D. An in-depth look at Krukenberg tumor: an overview. Arch. Pathol. Lab. Med. 130, 1725–1730 (2006).
pubmed: 17076540
doi: 10.5858/2006-130-1725-AILAKT
Wellenstein, M. D. et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature https://doi.org/10.1038/s41586-019-1450-6 (2019).
doi: 10.1038/s41586-019-1450-6
pubmed: 31367040
pmcid: 6707815
Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).
pubmed: 27015306
pmcid: 4808520
doi: 10.1016/j.cell.2016.02.025
Lopez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).
pubmed: 28810142
doi: 10.1016/j.ccell.2017.06.009
Tsukamoto, T., Mizoshita, T. & Tatematsu, M. Animal models of stomach carcinogenesis. Toxicol. Pathol. 35, 636–648 (2007).
pubmed: 17654405
doi: 10.1080/01926230701420632
Yamamoto, M. et al. Independent variation in susceptibilities of six different mouse strains to induction of pepsinogen-altered pyloric glands and gastric tumor intestinalization by N-methyl-N-nitrosourea. Cancer Lett. 179, 121–132 (2002).
pubmed: 11888666
doi: 10.1016/S0304-3835(02)00013-7
Saenz, J. B., Burclaff, J. & Mills, J. C. Modeling murine gastric metaplasia through tamoxifen-induced acute parietal cell loss. Methods Mol. Biol. 1422, 329–339 (2016).
pubmed: 27246044
pmcid: 5221414
doi: 10.1007/978-1-4939-3603-8_28
Shibata, W. et al. Conditional deletion of IκB-kinase-β accelerates helicobacter-dependent gastric apoptosis, proliferation, and preneoplasia. Gastroenterology 138, 1022–1034 (2010).
pubmed: 19962981
doi: 10.1053/j.gastro.2009.11.054
Qi, C. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat. Med. 28, 1189–1198 (2022).
pubmed: 35534566
pmcid: 9205778
doi: 10.1038/s41591-022-01800-8
Wainberg, Z. A. et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 23, 1430–1440 (2022).
pubmed: 36244398
doi: 10.1016/S1470-2045(22)00603-9
Tanaka, Y. et al. Multi-omic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities. Nat. Cancer 2, 962–977 (2021).
pubmed: 35121863
doi: 10.1038/s43018-021-00240-6
Sathe, P. et al. Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells. Nat. Commun. 5, 4539 (2014).
pubmed: 25119382
doi: 10.1038/ncomms5539
Smyth, M. J. et al. Perforin is a major contributor to NK cell control of tumor metastasis. J. Immunol. 162, 6658–6662 (1999).
pubmed: 10352283
doi: 10.4049/jimmunol.162.11.6658
Gryfe, R. et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N. Engl. J. Med. 342, 69–77 (2000).
pubmed: 10631274
doi: 10.1056/NEJM200001133420201
Malesci, A. et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin. Cancer Res. 13, 3831–3839 (2007).
pubmed: 17606714
doi: 10.1158/1078-0432.CCR-07-0366
Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).
pubmed: 15894267
doi: 10.1016/j.ccr.2005.04.023
Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).
pubmed: 24695404
pmcid: 4103590
doi: 10.1093/bioinformatics/btu170
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
pubmed: 24227677
doi: 10.1093/bioinformatics/btt656
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinf. 14, 128 (2013).
doi: 10.1186/1471-2105-14-128
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102
Foroutan, M. et al. Single sample scoring of molecular phenotypes. BMC Bioinform. 19, 404 (2018).
doi: 10.1186/s12859-018-2435-4
Baslan, T. et al. Genome-wide copy number analysis of single cells. Nat. Protoc. 7, 1024–1041 (2012).
pubmed: 22555242
pmcid: 5069701
doi: 10.1038/nprot.2012.039
Baslan, T. et al. Optimizing sparse sequencing of single cells for highly multiplex copy number profiling. Genome Res. 25, 714–724 (2015).
pubmed: 25858951
pmcid: 4417119
doi: 10.1101/gr.188060.114
Colaprico, A. et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 44, e71 (2016).
pubmed: 26704973
doi: 10.1093/nar/gkv1507
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
pubmed: 25605792
pmcid: 4402510
doi: 10.1093/nar/gkv007
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
pubmed: 22588877
doi: 10.1158/2159-8290.CD-12-0095
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
pubmed: 23550210
pmcid: 4160307
doi: 10.1126/scisignal.2004088