Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2021

01-12-2021 | Metastasis | Research

High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

Authors: Bo Ren, Jinshou Yang, Chengcheng Wang, Gang Yang, Huanyu Wang, Yuan Chen, Ruiyuan Xu, Xuning Fan, Lei You, Taiping Zhang, Yupei Zhao

Published in: Journal of Hematology & Oncology | Issue 1/2021

Login to get access

Abstract

Background

Pancreatic cancer’s poor prognosis is caused by distal metastasis, which is associated with epigenetic changes. However, the role of the 3D epigenome in pancreatic cancer biology, especially its metastasis, remains unclear.

Methods

Here, we developed high-resolution 3D epigenomic maps of cells derived from normal pancreatic epithelium, primary and metastatic pancreatic cancer by in situ Hi-C, ChIP-seq, ATAC-seq, and RNA-seq to identify key genes involved in pancreatic cancer metastasis

Results

We found that A/B compartments, contact domains, and chromatin loops changed significantly in metastatic pancreatic cancer cells, which are associated with epigenetic state alterations. Moreover, we found that upregulated genes, which were located in switched compartments, changed contact domains, and metastasis-specific enhancer-promoter loops, were related to cancer metastasis and poor prognosis of patients with pancreatic cancer. We also found that transcription factors in specific enhancer-promoter loop formation were also associated with metastasis. Finally we demonstrated that LIPC, looped to metastasis-specific enhancers, could promote pancreatic cancer metastasis.

Conclusions

These results highlight the multiscale 3D epigenome reprogramming during pancreatic cancer metastasis and expand our knowledge of mechanisms of gene regulation during pancreatic cancer metastasis.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.PubMed
2.
3.
Makohon-Moore AP, Zhang M, Reiter JG, Bozic I, Allen B, Kundu D, Chatterjee K, Wong F, Jiao Y, Kohutek ZA, et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet. 2017;49:358–66.CrossRefPubMedPubMedCentral
4.
Lomberk G, Blum Y, Nicolle R, Nair A, Gaonkar KS, Marisa L, Mathison A, Sun Z, Yan H, Elarouci N, et al. Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. Nat Commun. 1978;2018:9.
5.
Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 2018;378:1323–34.CrossRefPubMed
6.
Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326:289–93.CrossRefPubMedPubMedCentral
7.
Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376–80.CrossRefPubMedPubMedCentral
8.
Rao SSP, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, Sanborn AL, Machol I, Omer AD, Lander ES, Aiden EL. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159:1665–80.CrossRefPubMedPubMedCentral
9.
Taberlay PC, Achinger-Kawecka J, Lun AT, Buske FA, Sabir K, Gould CM, Zotenko E, Bert SA, Giles KA, Bauer DC, et al. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations. Genome Res. 2016;26:719–31.CrossRefPubMedPubMedCentral
10.
Rhie SK, Perez AA, Lay FD, Schreiner S, Shi J, Polin J, Farnham PJ. A high-resolution 3D epigenomic map reveals insights into the creation of the prostate cancer transcriptome. Nat Commun. 2019;10:4154.CrossRefPubMedPubMedCentral
11.
Zhao T, Jiang W, Wang X, Wang H, Zheng C, Li Y, Sun Y, Huang C, Han ZB, Yang S, et al. ESE3 inhibits pancreatic cancer metastasis by upregulating E-cadherin. Cancer Res. 2017;77:874–85.CrossRefPubMed
12.
Du Y, Liu Z, You L, Hou P, Ren X, Jiao T, Zhao W, Li Z, Shu H, Liu C, Zhao Y. Pancreatic cancer progression relies upon mutant p53-induced oncogenic signalling mediated by NOP14. Cancer Res. 2017;77:2661–73.CrossRefPubMed
13.
Servant N, Varoquaux N, Lajoie BR, Viara E, Chen CJ, Vert JP, Heard E, Dekker J, Barillot E. HiC-Pro: an optimized and flexible pipeline for Hi-C data processing. Genome Biol. 2015;16:259.CrossRefPubMedPubMedCentral
14.
Yang T, Zhang F, Yardimci GG, Song F, Hardison RC, Noble WS, Yue F, Li Q. HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient. Genome Res. 2017;27:1939–49.CrossRefPubMedPubMedCentral
15.
Hagege H, Klous P, Braem C, Splinter E, Dekker J, Cathala G, de Laat W, Forne T. Quantitative analysis of chromosome conformation capture assays (3C-qPCR). Nat Protoc. 2007;2:1722–33.CrossRefPubMed
16.
Concordet JP, Haeussler M. CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucl Acids Res. 2018;46:W242–5.CrossRefPubMedPubMedCentral
17.
Williams RM, Senanayake U, Artibani M, Taylor G, Wells D, Ahmed AA, Sauka-Spengler T. Genome and epigenome engineering CRISPR toolkit for in vivo modulation of cis-regulatory interactions and gene expression in the chicken embryo. Development 2018;145:dev160333.
18.
Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 2013;14:7.CrossRef
19.
Van den Broeck A, Vankelecom H, Van Eijsden R, Govaere O, Topal B. Molecular markers associated with outcome and metastasis in human pancreatic cancer. J Exp Clin Cancer Res. 2012;31:68.CrossRefPubMedPubMedCentral
20.
McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, Word AE, Carrer A, Salz TH, Natsume S, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017;49:367–76.CrossRefPubMedPubMedCentral
21.
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
22.
Roe JS, Hwang CI, Somerville TDD, Milazzo JP, Lee EJ, Da Silva B, Maiorino L, Tiriac H, Young CM, Miyabayashi K, et al. Enhancer reprogramming promotes pancreatic cancer metastasis. Cell. 2017;170:875–88.CrossRefPubMedPubMedCentral
23.
Dixon JR, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget JE, Lee AY, Ye Z, Kim A, Rajagopal N, Xie W, et al. Chromatin architecture reorganization during stem cell differentiation. Nature. 2015;518:331–6.CrossRefPubMedPubMedCentral
24.
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.CrossRefPubMedPubMedCentral
25.
Mueller S, Engleitner T, Maresch R, Zukowska M, Lange S, Kaltenbacher T, Konukiewitz B, Ollinger R, Zwiebel M, Strong A, et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature. 2018;554:62–8.CrossRefPubMedPubMedCentral
26.
Zufferey M, Tavernari D, Oricchio E, Ciriello G. Comparison of computational methods for the identification of topologically associating domains. Genome Biol. 2018;19:217.CrossRefPubMedPubMedCentral
27.
Kibe S, Ohuchida K, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Okumura T, Iwamoto C, et al. Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion. Cancer Lett. 2019;444:70–81.CrossRefPubMed
28.
Schoenfelder S, Fraser P. Long-range enhancer-promoter contacts in gene expression control. Nat Rev Genet. 2019;20:437–55.CrossRefPubMed
29.
Andersson R, Sandelin A. Determinants of enhancer and promoter activities of regulatory elements. Nat Rev Genet. 2020;21:71–87.CrossRefPubMed
30.
Rowley MJ, Corces VG. Organizational principles of 3D genome architecture. Nat Rev Genet. 2018;19:789–800.CrossRefPubMed
31.
Zhong J, Jermusyk A, Wu L, Hoskins JW, Collins I, Mocci E, Zhang M, Song L, Chung CC, Zhang T, et al. A transcriptome-wide association study (TWAS) identifies novel candidate susceptibility genes for pancreatic cancer. J Natl Cancer Inst. 2020;112:1003-1012.
32.
He P, Yang JW, Yang VW, Bialkowska AB. Kruppel-like factor 5, increased in pancreatic ductal adenocarcinoma, promotes proliferation, acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia, and tumor growth in mice. Gastroenterology. 2018;154:1494–508.CrossRefPubMed
33.
Dixon JR, Xu J, Dileep V, Zhan Y, Song F, Le VT, Yardimci GG, Chakraborty A, Bann DV, Wang Y, et al. Integrative detection and analysis of structural variation in cancer genomes. Nat Genet. 2018;50:1388–98.CrossRefPubMedPubMedCentral
34.
Gerrard DL, Boyd JR, Stein GS, Jin VX, Frietze S. Disruption of broad epigenetic domains in PDAC cells by HAT inhibitors. Epigenomes. 2019;3:11.
35.
Gerrard DL, Wang Y, Gaddis M, Zhou Y, Wang J, Witt H, Lin S, Farnham PJ, Jin VX, Frietze SE. Three-dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2-regulated cancer gene signature. J Cell Biochem. 2019;120:3056–70.CrossRefPubMed
36.
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.CrossRefPubMedPubMedCentral
37.
Akdemir KC, Le VT, Chandran S, Li Y, Verhaak RG, Beroukhim R, Campbell PJ, Chin L, Dixon JR, Futreal PA, et al. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nat Genet. 2020;52:294–305.CrossRefPubMedPubMedCentral
38.
Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2012;9:454–67.CrossRefPubMed
39.
Schild T, Low V, Blenis J, Gomes AP. Unique metabolic adaptations dictate distal organ-specific metastatic colonization. Cancer Cell. 2018;33:347–54.CrossRefPubMedPubMedCentral
Metadata
Title
High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis
Authors
Bo Ren
Jinshou Yang
Chengcheng Wang
Gang Yang
Huanyu Wang
Yuan Chen
Ruiyuan Xu
Xuning Fan
Lei You
Taiping Zhang
Yupei Zhao
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2021
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-021-01131-0

Other articles of this Issue 1/2021

Journal of Hematology & Oncology 1/2021 Go to the issue

Research

Predictors of neutralizing antibody response to BNT162b2 vaccination in allogeneic hematopoietic stem cell transplant recipients

Review

COVID-19 vaccines for patients with cancer: benefits likely outweigh risks

Letter to the Editor

Kynurenine derivative 3-HAA is an agonist ligand for transcription factor YY1

Research

Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers

Correction

Correction to: Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

Review

Mesenchymal stem/stromal cells in cancer therapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits