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Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

Reprogramming of stromal fibroblasts by SNAI2 contributes to tumor desmoplasia and ovarian cancer progression

Authors: Zongyuan Yang, Xin Yang, Sen Xu, Ping Jin, Xiaoting Li, Xiao Wei, Dan Liu, Kecheng Huang, Sixiang Long, Ya Wang, Chaoyang Sun, Gang Chen, Junbo Hu, Li Meng, Ding Ma, Qinglei Gao

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Background

Molecular profiling in ovarian cancer (OC) revealed that the desmoplasia subtype presented the poorest prognosis, highlighting the contribution of stromal fibroblasts in tumor progression. This study aimed to investigate the molecular characteristics of SNAI2 driving the transcriptional reprogramming of fibroblasts within tumors.

Methods

SNAI2 expression was evaluated in microdissected profiles of various cancers and in various molecular subtypes of OC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were performed to explore the correlation between SNAI2 and stromal fibroblast activation. The SNAI2 defined signature in the mesenchymal OC subtype was identified through an integrative analysis of the TCGA and the Tothill datasets. The predictive value of this signature was validated in independent datasets. SNAI2 expression alteration influence of tumor growth in primary CAFs was evaluated in 3D organotypic and murine xenograft models.

Results

We demonstrated that SNAI2 was frequently activated in the tumor stroma, correlated with fibroblast activation and worse patient outcome in OC. SNAI2 transformed normal fibroblasts to a CAF-like state and boosted their tumor–supporting role in 3D organotypic culture and in OC xenograft model. SNAI2 drove a transcriptional signature in the mesenchymal subtype of OC that contributed to tumor desmoplasia, which fed back to increase SNAI2 expression and sustain fibroblast activation.

Conclusions

Our results address the role of SNAI2 in reprogramming stromal fibroblasts. The identified SNAI2 mesenchymal signature has both a predictive value and biological relevance and might be a therapeutic target for stroma-oriented therapy against the desmoplasia OC subtype.
Appendix
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Literature
1.
Bowtell DD. The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer. 2010;10:803–8.CrossRefPubMed
2.
Vang R, Shih Ie M, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol. 2009;16:267–82.CrossRefPubMedPubMedCentral
3.
De Sousa E, Melo F, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LP, de Jong JH, de Boer OJ, van Leersum R, Bijlsma MF, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013;19:614–8.CrossRef
4.
Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, Johnson DS, Trivett MK, Etemadmoghadam D, Locandro B, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 2008;14:5198–208.CrossRefPubMed
5.
Bell D, Berchuck A, Birrer M, Chien J, Cramer D, Dao F, Dhir R, DiSaia P, Gabra H, Glenn P, et al. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.CrossRef
6.
Whatcott CJ, Diep CH, Jiang P, Watanabe A, LoBello J, Sima C, Hostetter G, Shepard HM, Von Hoff DD, Han H. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res. 2015;21:3561–8.CrossRefPubMedPubMedCentral
7.
8.
Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, et al. Virtual microdissection identifies distinct tumor-and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47:1168–78.CrossRefPubMedPubMedCentral
9.
Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, CC W, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.CrossRefPubMedPubMedCentral
10.
Calvo F, Ranftl R, Hooper S, Farrugia AJ, Moeendarbary E, Bruckbauer A, Batista F, Charras G, Sahai E. Cdc42EP3/BORG2 and Septin network enables Mechano-transduction and the emergence of cancer-associated fibroblasts. Cell Rep. 2015;13:2699–714.CrossRefPubMedPubMedCentral
11.
Ren Y, Zhou X, Liu X, Jia HH, Zhao XH, Wang QX, Han L, Song X, Zhu ZY, Sun T, et al. Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy. Cancer Lett. 2016;374:96–106.CrossRefPubMed
12.
Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, Harrington K, Williamson P, Moeendarbary E, Charras G, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013;15:637–46.CrossRefPubMed
13.
Zhang Y, Tang H, Cai J, Zhang T, Guo J, Feng D, Wang Z. Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett. 2011;303:47–55.CrossRefPubMed
14.
Van Oevelen C, Kallin EM, Graf T. Transcription factor-induced enhancer modulations during cell fate conversions. Curr Opin Genet Dev. 2013;23:562–7.CrossRefPubMed
15.
Lee KW, Yeo SY, Sung CO, Kim SH. Twist1 is a key regulator of cancer-associated fibroblasts. Cancer Res. 2015;75:73–85.CrossRefPubMed
16.
Huynh TG, Morales-Oyarvide V, Campo MJ, Gainor JF, Bozkurtlar E, Uruga H, Zhao L, Gomez-Caraballo M, Hata AN, Mark EJ, et al. Programmed cell death Ligand 1 expression in Resected lung Adenocarcinomas: association with immune microenvironment. J Thorac Oncol. 2016;11:1869–78.CrossRefPubMed
17.
Herrera A, Herrera M, Peña C. The emerging role of Snail1 in the tumor stroma. Clin Transl Oncol. 2016;18:872–7.CrossRefPubMed
18.
Stanisavljevic J, Loubat-Casanovas J, Herrera M, Luque T, Peña R, Lluch A, Albanell J, Bonilla F, Rovira A, Peña C, et al. Snail1-expressing fibroblasts in the tumor microenvironment display mechanical properties that support metastasis. Cancer Res. 2015;75:284–95.CrossRefPubMed
19.
Zhang K, Grither WR, Van Hove S, Biswas H, Ponik SM, Eliceiri KW, Keely PJ, Longmore GD. Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts. J Cell Sci. 2016;129:1989–2002.CrossRefPubMedPubMedCentral
20.
Peña C, Céspedes MV, Lindh MB, Kiflemariam S, Mezheyeuski A, Edqvist PH, Hägglöf C, Birgisson H, Bojmar L, Jirström K, et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res. 2013;73:1287–97.CrossRefPubMed
21.
Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, Fereday S, Lawrence M, Carter SL, Mermel CH, et al. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 2013;123:517–25.PubMed
22.
Yang Z, Xu S, Jin P, Yang X, Li X, Wan D, Zhang T, Long S, Wei X, Chen G, et al. MARCKS contributes to stromal cancer-associated fibroblast activation and facilitates ovarian cancer metastasis. Oncotarget. 2016;7:37649–63.CrossRefPubMedPubMedCentral
23.
Valencia T, Kim JY, Abu-Baker S, Moscat-Pardos J, Ahn CS, Reina-Campos M, Duran A, Castilla EA, Metallo CM, Diaz-Meco MT, et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell. 2014;26:121–35.CrossRefPubMedPubMedCentral
24.
Huang CR, Lee CT, Chang KY, Chang WC, Liu YW, Lee JC, Chen BK. Down-regulation of ARNT promotes cancer metastasis by activating the fibronectin/integrin beta1/FAK axis. Oncotarget. 2015;6:11530–46.CrossRefPubMedPubMedCentral
25.
Ganzfried BF, Riester M, Haibe-Kains B, Risch T, Tyekucheva S, Jazic I, Wang XV, Ahmadifar M, Birrer MJ, Parmigiani G, et al. curatedOvarianData: clinically annotated data for the ovarian cancer transcriptome. Database (Oxford). 2013:bat013. doi:10.​1093/​database/​bat013. Print 2013.
26.
White EA, Kenny HA, Lengyel E. Three-dimensional modeling of ovarian cancer. Adv Drug Deliv Rev. 2014;79-80:184–92.CrossRefPubMed
27.
28.
You Y, Zheng Q, Dong Y, Xie X, Wang Y, Wu S, Zhang L, Wang Y, Xue T, Wang Z, et al. Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells. Oncotarget. 2016;7:32221–31.CrossRefPubMedPubMedCentral
29.
Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, Nair VS, Xu Y, Khuong A, Hoang CD, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21:938–45.CrossRefPubMedPubMedCentral
30.
Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–84.CrossRefPubMedPubMedCentral
31.
Waghray M, Yalamanchili M, Dziubinski M, Zeinali M, Erkkinen M, Yang H, Schradle KA, Urs S, Pasca Di Magliano M, Welling TH, et al. GM-CSF mediates Mesenchymal-epithelial cross-talk in pancreatic cancer. Cancer Discov. 2016;6:886–99.CrossRefPubMedPubMedCentral
32.
Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN, Acerbi I, Ou G, Wijekoon AC, Levental KR, Gilbert PM, et al. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med. 2014;20:360–7.CrossRefPubMedPubMedCentral
33.
Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell. 2013;154:1047–59.CrossRefPubMed
34.
Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, Shao YW, Aiken A, Waterhouse PD, Karamboulas C, et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat Cell Biol. 2014;16:889–901.CrossRefPubMed
35.
Xiao Q, Zhou D, Rucki AA, Williams J, Zhou J, Mo G, Murphy A, Fujiwara K, Kleponis J, Salman B, et al. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA Methylation. Cancer Res. 2016;76:5395–404.CrossRefPubMedPubMedCentral
36.
Côme C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, Savagner P. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res. 2006;12:5395–402.CrossRefPubMed
37.
Casas E, Kim J, Bendesky A, Ohno-Machado L, Wolfe CJ, Yang J. Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res. 2011;71:245–54.CrossRefPubMedPubMedCentral
38.
Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, Hudson LG. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol. 2005;202:858–66.CrossRefPubMed
39.
Hemavathy K, Ashraf SI, Ip YT. Snail/slug family of repressors: slowly going into the fast lane of development and cancer. Gene. 2000;257:1–12.CrossRefPubMed
40.
Samanta S, Sun H, Goel HL, Pursell B, Chang C, Khan A, Greiner DL, Cao S, Lim E, Shultz LD, et al. IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene. 2016;35:1111–21.CrossRefPubMed
41.
Luanpitpong S, Li J, Manke A, Brundage K, Ellis E, McLaughlin SL, Angsutararux P, Chanthra N, Voronkova M, Chen YC, et al. SLUG is required for SOX9 stabilization and functions to promote cancer stem cells and metastasis in human lung carcinoma. Oncogene. 2016;35:2824–33.CrossRefPubMed
42.
Del Pozo Martin Y, Park D, Ramachandran A, Ombrato L, Calvo F, Chakravarty P, Spencer-Dene B, Derzsi S, Hill CS, Sahai E, et al. Mesenchymal cancer cell-Stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 2015;13:2456–69.CrossRefPubMedPubMedCentral
43.
Cheon DJ, Tong Y, Sim MS, Dering J, Berel D, Cui X, Lester J, Beach JA, Tighiouart M, Walts AE, et al. A collagen-remodeling gene signature regulated by TGF-beta signaling is associated with metastasis and poor survival in serous ovarian cancer. Clin Cancer Res. 2014;20:711–23.CrossRefPubMed
44.
Ryner L, Guan Y, Firestein R, Xiao Y, Choi Y, Rabe C, Lu S, Fuentes E, Huw LY, Lackner MR, et al. Upregulation of Periostin and reactive Stroma is associated with primary Chemoresistance and predicts clinical outcomes in epithelial ovarian cancer. Clin Cancer Res. 2015;21:2941–51.CrossRefPubMed
45.
Metadata
Title
Reprogramming of stromal fibroblasts by SNAI2 contributes to tumor desmoplasia and ovarian cancer progression
Authors
Zongyuan Yang
Xin Yang
Sen Xu
Ping Jin
Xiaoting Li
Xiao Wei
Dan Liu
Kecheng Huang
Sixiang Long
Ya Wang
Chaoyang Sun
Gang Chen
Junbo Hu
Li Meng
Ding Ma
Qinglei Gao
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0732-6

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