Skip to main content

Advertisement

SpringerLink
Log in

LncRNAs associated with vascular mimicry establish a novel molecular subtype and prognostic model for pancreatic cancer

  • Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Vascular mimicry (VM) epitomizes an innovative tumor angiogenesis pathway, potentially serving as an alternate conduit under the assumption of traditional tumor angiogenesis pathway inhibition. The role of VM in pancreatic cancer (PC), however, remains unexplored.

Methods

Using differential analysis and Spearman correlation, we identified key long non-coding RNAs (lncRNAs) signatures in PC from the collected set of VM-associated genes in the literature. We identified optimal clusters using the non-negative matrix decomposition (NMF) algorithm, and then compared clinicopathological features and prognostic differences between clusters. We also assessed tumor microenvironmental (TME) differences between clusters using multiple algorithms. Using univariate Cox regression analyses as well as lasso regression, we constructed and validated new lncRNA prognostic risk models for PC. We used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze model-enriched functions and pathways. Nomograms were then developed to predict patient survival in association with clinicopathological factors. In addition, single-cell RNA-sequencing (scRNA-seq) analysis was used to analyze the expression patterns of VM-related genes and lncRNAs in the PC of TME. Finally, we used the Connectivity Map (cMap) database to predict local anaesthetics that could modify the VM of PC.

Results

In this study, we developed a novel three-cluster molecular subtype using the identified VM-associated lncRNA signatures of PC. The different subtypes have significantly different clinical characteristics and prognostic value, and also show differential treatment response and TME. Following an in-depth analysis, we constructed and validated a novel prognostic risk model for PC based on the VM-associated lncRNA signatures. Enrichment analysis suggested that high riskscores were significantly associated with functions and pathways, including extracellular matrix remodeling, et al. In addition, we predicted eight local anaesthetics that could modulate VM in PC. Finally, we discovered differential expression of VM-related genes and lncRNAs across various cell types within pancreatic cancer.

Conclusion

VM has a critical role in PC. This study pioneers the development of a VM-based molecular subtype that demonstrates substantial differentiation in PC populations. Furthermore, we highlighted the significance of VM within the immune microenvironment of PC. Moreover, VM might contribute to PC tumorigenesis through its mediation of mesenchymal remodeling and endothelial transdifferentiation-related pathways, which offers a new perspective on its role in PC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Availability of data and materials

The datasets analyzed during the current study are available in the Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/), the Genotype-Tissue Expression (GTEx) project (https://xenabrowser.net/hub/), and the International Cancer Genome Consortium (ICGC) (https://daco.icgc.org/).

References

  • Andonegui-Elguera MA, Alfaro-Mora Y, Cáceres-Gutiérrez R, Caro-Sánchez CHS, Herrera LA, Díaz-Chávez J (2020) An overview of vasculogenic mimicry in breast cancer. Front Oncol 10:220

    PubMed  PubMed Central  Google Scholar 

  • Angara K, Borin TF, Arbab AS (2017) Vascular mimicry: a novel neovascularization mechanism driving anti-angiogenic therapy (AAT) resistance in glioblastoma. Translat Oncol 10(4):650–660

    Google Scholar 

  • Basu GD, Liang WS, Stephan DA, Wegener LT, Conley CR, Pockaj BA, Mukherjee P (2006) A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. Breast Cancer Res 8(6):R69

    PubMed  PubMed Central  Google Scholar 

  • Brunner M, Wu Z, Krautz C, Pilarsky C, Grützmann R, Weber GF (2019) Current clinical strategies of pancreatic cancer treatment and open molecular questions. Int J Mol Sci 20(18):4543

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cata JP, Sood AK, Eltzschig HK (2020) Anesthetic drugs and cancer progression. Anesthesiology 133(4):698–699

    CAS  PubMed  Google Scholar 

  • Ding J, Jia X, Zuo B, He J, Yang J, He Y (2018) A novel monoclonal antibody targeting a novel epitope of VE-cadherin inhibits vasculogenic mimicry of lung cancer cells. Oncol Rep 39(6):2837–2844

    CAS  PubMed  Google Scholar 

  • Ezashi T, Das P, Roberts RM (2005) Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci USA 102(13):4783–4788

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gaujoux R, Seoighe C (2010) A flexible R package for nonnegative matrix factorization. BMC Bioinform 11:367

    Google Scholar 

  • Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G et al (2011) Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res 17(23):7337–7346

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hendrix MJ, Seftor RE, Seftor EA, Gruman LM, Lee LM, Nickoloff BJ, Miele L, Sheriff DD, Schatteman GC (2002) Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination. Cancer Res 62(3):665–668

    CAS  PubMed  Google Scholar 

  • Hess AR, Seftor EA, Seftor RE, Hendrix MJ (2003) Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. Cancer Res 63(16):4757–4762

    CAS  PubMed  Google Scholar 

  • Hess AR, Seftor EA, Gruman LM, Kinch MS, Seftor RE, Hendrix MJ (2006) VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway: implications for vasculogenic mimicry. Cancer Biol Ther 5(2):228–233

    CAS  PubMed  Google Scholar 

  • Huang L, Jansen L, Balavarca Y, Molina-Montes E, Babaei M, van der Geest L, Lemmens V, Van Eycken L, De Schutter H, Johannesen TB et al (2019) Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut 68(1):130–139

    PubMed  Google Scholar 

  • Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B et al (2018) Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 24(10):1550–1558

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang S, Fagman JB, Ma Y, Liu J, Vihav C, Engstrom C, Liu B, Chen C (2022) A comprehensive review of pancreatic cancer and its therapeutic challenges. Aging 14(18):7635–7649

    PubMed  PubMed Central  Google Scholar 

  • Liu W, Chen Y, Xu W, Wang W, Tang L, Xia R, Zhu Q (2020) Fentanyl stimulates tumor angiogenesis via activating multiple pro-angiogenic signaling pathways. Biochem Biophys Res Commun 532(2):225–230

    CAS  PubMed  Google Scholar 

  • Liu M, Ruan X, Liu X, Dong W, Wang D, Yang C, Liu L, Wang P, Zhang M, Xue Y (2022) The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells. Cell Death Dis 13(12):1017

    CAS  PubMed  PubMed Central  Google Scholar 

  • Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550

    PubMed  PubMed Central  Google Scholar 

  • Mizrahi JD, Surana R, Valle JW, Shroff RT (2020) Pancreatic cancer. The Lancet 395(10242):2008–2020

    CAS  Google Scholar 

  • Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453–457

    CAS  PubMed  PubMed Central  Google Scholar 

  • Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science (New York, NY) 324(5933):1457–1461

    CAS  Google Scholar 

  • Ouyang G, Wu Y, Liu Z, Lu W, Li S, Hao S, Pan G (2021) Efficacy and safety of gemcitabine-capecitabine combination therapy for pancreatic cancer: A systematic review and meta-analysis of randomized controlled trials. Medicine 100(48):e27870

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ramsay IS, Ma S, Fisher M, Loewy RL, Ragland JD, Niendam T, Carter CS, Vinogradov S (2018) Model selection and prediction of outcomes in recent onset schizophrenia patients who undergo cognitive training. Schizophrenia Res Cogn 11:1–5

    Google Scholar 

  • Seftor RE, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV, Hendrix MJ (2012) Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol 181(4):1115–1125

    CAS  PubMed  PubMed Central  Google Scholar 

  • Subramanian A, Narayan R, Corsello SM, Peck DD, Natoli TE, Lu X, Gould J, Davis JF, Tubelli AA, Asiedu JK et al (2017) A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171(6):1437-1452.e1417

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA 71(3):209–249

  • Tang J, Bao M, Chen J, Bin X, Xu X, Fang X, Tang Z (2022) Long-noncoding RNA MANCR is associated with head and neck squamous cell carcinoma malignant development and immune infiltration. Front Genet 13:911733

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tao J, Yang G, Zhou W, Qiu J, Chen G, Luo W, Zhao F, You L, Zheng L, Zhang T et al (2021) Targeting hypoxic tumor microenvironment in pancreatic cancer. J Hematol Oncol 14(1):14

    PubMed  PubMed Central  Google Scholar 

  • Thummuri D, Khan S, Underwood PW, Zhang P, Wiegand J, Zhang X, Budamagunta V, Sobh A, Tagmount A, Loguinov A et al (2022) Overcoming gemcitabine resistance in pancreatic cancer using the BCL-X(L)-specific degrader DT2216. Mol Cancer Ther 21(1):184–192

    CAS  PubMed  Google Scholar 

  • van Beijnum JR, Nowak-Sliwinska P, Huijbers EJ, Thijssen VL, Griffioen AW (2015) The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev 67(2):441–461

    PubMed  Google Scholar 

  • Wang M, Zhao X, Zhu D, Liu T, Liang X, Liu F, Zhang Y, Dong X, Sun B (2017) HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment. J Exp Clin Cancer Res 36(1):60

    PubMed  PubMed Central  Google Scholar 

  • Wang Z, Cao B, Ji P, Yao F (2021) Propofol inhibits tumor angiogenesis through targeting VEGF/VEGFR and mTOR/eIF4E signaling. Biochem Biophys Res Commun 555:13–18

    CAS  PubMed  Google Scholar 

  • Wang J, Xia W, Huang Y, Li H, Tang Y, Li Y, Yi B, Zhang Z, Yang J, Cao Z et al (2022) A vasculogenic mimicry prognostic signature associated with immune signature in human gastric cancer. Front Immunol 13:1016612

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wei F, Wang D, Wei J, Tang N, Tang L, Xiong F, Guo C, Zhou M, Li X, Li G et al (2021a) Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance. Cell Mol Life Sci CMLS 78(1):173–193

    CAS  PubMed  Google Scholar 

  • Wei X, Chen Y, Jiang X, Peng M, Liu Y, Mo Y, Ren D, Hua Y, Yu B, Zhou Y et al (2021b) Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments. Mol Cancer 20(1):7

    PubMed  PubMed Central  Google Scholar 

  • Williamson SC, Metcalf RL, Trapani F, Mohan S, Antonello J, Abbott B, Leong HS, Chester CP, Simms N, Polanski R et al (2016) Vasculogenic mimicry in small cell lung cancer. Nat Commun 7:13322

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu C, Sui S, Shang Y, Yu Z, Han J, Zhang G, Ntim M, Hu M, Gong P, Chen H et al (2020) The landscape of immune cell infiltration and its clinical implications of pancreatic ductal adenocarcinoma. J Adv Res 24:139–148

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang JP, Liao YD, Mai DM, Xie P, Qiang YY, Zheng LS, Wang MY, Mei Y, Meng DF, Xu L et al (2016) Tumor vasculogenic mimicry predicts poor prognosis in cancer patients: a meta-analysis. Angiogenesis 19(2):191–200

    CAS  PubMed  Google Scholar 

  • Yang J, Li G, Bao K, Liu W, Zhang Y, Ting W (2019) Ropivacaine inhibits tumor angiogenesis via sodium-channel-independent mitochondrial dysfunction and oxidative stress. J Bioenerg Biomembr 51(3):231–238

    CAS  PubMed  Google Scholar 

  • Yang W, Li Z, Wang W, Wu J, Li J, Huang X, Zhang X, Ye X (2023) Vasculogenic mimicry score identifies the prognosis and immune landscape of lung adenocarcinoma. Front Genet 14

  • Yeo C, Lee HJ, Lee EO (2019) Serum promotes vasculogenic mimicry through the EphA2/VE-cadherin/AKT pathway in PC-3 human prostate cancer cells. Life Sci 221:267–273

    CAS  PubMed  Google Scholar 

  • Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, Treviño V, Shen H, Laird PW, Levine DA et al (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612

    PubMed  Google Scholar 

  • Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16(5):284–287

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yura Y, Chong BSH, Johnson RD, Watanabe Y, Tsukahara Y, Ferran B, Murdoch CE, Behring JB, McComb ME, Costello CE et al (2019) Endothelial cell-specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice. FASEB J 33(12):14147–14158

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Zhang J, Zhou H, Fan G, Li Q (2019) Molecular mechanisms and anticancer therapeutic strategies in vasculogenic mimicry. J Cancer 10(25):6327–6340

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Feng H, Yu T, Zhang M, Liu Z, Ma L, Liu H (2023) Construction of an oxidative stress-related lncRNAs signature to predict prognosis and the immune response in gastric cancer. Sci Rep 13(1):8822

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng QM, Li YY, Wang YP, Li GX, Zhao MM, Sun ZG (2023) Association between CD8+ tumor-infiltrating lymphocytes and prognosis of non-small cell lung cancer patients treated with PD-1/PD-L1 inhibitors: a systematic review and meta-analysis. Expert Rev Anticancer Ther 23(6):643–659

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all the reviewers who participated in the review.

Funding

This study did not receive any funding.

Author information

Author notes

  1. Qiang Zhang and Yubao Tang contributed equally to this work.

Authors and Affiliations

  1. Hepatobiliary Surgery Department, Yangzhou University Affiliated Hospital, Yangzhou, 225000, Jiangsu, China

    Da Li, Feiyu Mao, Jia Zeng & Anlai Ji

  2. Medical College of Yangzhou University, Yangzhou, 225000, Jiangsu, China

    Qiang Zhang & Yubao Tang

Authors
  1. Da Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yubao Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feiyu Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anlai Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, DL, Methodology, DL and QZ, Software, QZ, Validation, YT and QZ, Formal analysis, DL. Investigation, FM and JZ. Resources, AJ. Writing—original draft preparation, DL. Writing—review and editing, JZ and YT. Visualization, FM. Supervision, AJ. Project administration, AJ.

Corresponding author

Correspondence to Anlai Ji.

Ethics declarations

Conflict of interest

None of the authors have any conflicts of interest to disclose.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

432_2023_5015_MOESM1_ESM.tif

Supplementary file1 (TIF 2807 KB) Fig S1: Independent Validation of the Novel lncRNA Prognostic Risk Model. A: The forest plot demonstrates significant prognostic value of the risk score, as determined by single-factor Cox regression analysis, in the test cohort (P < 0.001). B: Likewise, the forest plot exhibits a statistically significant prognostic value of the risk score after multi-factor Cox regression analysis in the test cohort (P < 0.001). C: The column line chart, constructed from multi-factor COX regression analysis results in the test cohort, forecasts patient survival probabilities at 1-year, 2-year, and 3-year intervals

432_2023_5015_MOESM2_ESM.tif

Supplementary file2 (TIF 4935 KB) Fig S2: Single-Cell RNA-Sequencing (scRNA-seq) analysis illustrates the distribution of VM-related lncRNAs expression in pancreatic cancer. A: A UMAP plot depicts the dispersal of VM-related gene expression across diverse cell clusters in PC. B: The differential distribution of VM-related genes across various cell clusters in tumor and normal tissues is demonstrated

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, D., Zhang, Q., Tang, Y. et al. LncRNAs associated with vascular mimicry establish a novel molecular subtype and prognostic model for pancreatic cancer. J Cancer Res Clin Oncol 149, 11571–11584 (2023). https://doi.org/10.1007/s00432-023-05015-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-023-05015-3

Keywords

Search

Navigation