1. Kleeff J, Korc M, Apte M, et al (2016) Pancreatic cancer. Nat Rev Dis Primers 2:16022. https://doi.org/10.1038/nrdp.2016.22
2. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30. https://doi.org/10.3322/caac.21442
3. Shi C, Hruban RH, Klein AP (2009) Familial pancreatic cancer. Arch Pathol Lab Med 133:365–374. https://doi.org/10.5858/133.3.365
4. Permuth-Wey J, Egan KM (2009) Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis. Fam Cancer 8:109–117. https://doi.org/10.1007/s10689-008-9214-8
5. Rahib L, Smith BD, Aizenberg R, et al (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921. https://doi.org/10.1158/0008-5472.can-14-0155
6. Wong MCS, Jiang JY, Liang M, et al (2017) Global temporal patterns of pancreatic cancer and association with socioeconomic development. Sci Rep 7:3165. https://doi.org/10.1038/s41598-017-02997-2
7. Neoptolemos JP, Cunningham D, Friess H, et al (2003) Adjuvant therapy in pancreatic cancer: historical and current perspectives. Ann Oncol 14:675–692. https://doi.org/10.1093/annonc/mdg207
8. Alexakis N, Halloran C, Raraty M, et (2004) Current standards of surgery for pancreatic cancer. Br J Surg 91:1410–1427. https://doi.org/10.1002/bjs.4794
9. Lee CJ, Li C, Simeone DM (2008) Human Pancreatic Cancer Stem Cells: Implications for How We Treat Pancreatic Cancer. Transl Oncol 1:14. https://doi.org/10.1593/tlo.08013
10. Samuel N, Hudson TJ (2011) The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 9:77–87. https://doi.org/10.1038/nrgastro.2011.215
11. Oberstein PE, Olive KP (2013) Pancreatic cancer: why is it so hard to treat? Therap Adv Gastroenterol 6:321–337. https://doi.org/10.1177/1756283x13478680
12. Almoguera C, Shibata D, Forrester K, et al (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554. https://doi.org/10.1016/0092-8674(88)90571-5
13. Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3:459–465. https://doi.org/10.1038/nrc1097
14. Rozenblum E, Schutte M, Goggins M, et al (1997) Tumor-suppressive Pathways in Pancreatic Carcinoma. Cancer Res 57.
15. Zheng L, Xue J, Jaffee EM, Habtezion A (2013) Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 144:1230–1240. https://doi.org/10.1053/j.gastro.2012.12.042
16. Khalafalla FG, Khan MW (2017) Inflammation and Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Fighting Against Multiple Opponents. Cancer Growth Metastasis 10:117906441770928. https://doi.org/10.1177/1179064417709287
17. Barrett T, Wilhite SE, Ledoux P, et al NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res 41. https://doi.org/10.1093/nar/gks1193
18. Athar A, Füllgrabe A, George N, et al (2019) ArrayExpress update - from bulk to single-cell expression data. Nucleic Acids Res 47:D711–D715. https://doi.org/10.1093/nar/gky964
19. Simon R, Lam A, Li M-C, et al (2007) Analysis of Gene Expression Data Using BRB-Array Tools. Cancer Inform 3:11-17. https://doi.org/10.1177/117693510700300022
20. Pathan M, Keerthikumar S, Ang CS, et al (2015) FunRich: An open access standalone functional enrichment and interaction network analysis tool. Proteomics 15:2597–2601. https://doi.org/10.1002/pmic.201400515
21. Hill DP, Smith B, McAndrews-Hill MS, et al (2008) Gene Ontology annotations: what they mean and where they come from. BMC Bioinformatics 2008 9:5 9:1–9. https://doi.org/10.1186/1471-2105-9-s5-s2
22. Schriml LM, Mitraka E, Munro J, et al (2019) Human Disease Ontology 2018 update: classification, content and workflow expansion. Nucleic Acids Res 47:D955–D962. https://doi.org/10.1093/nar/gky1032
23. Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30. https://doi.org/10.1093/nar/28.1.27
24. Yu G, Wang LG, Han Y, et al (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16:284–287. https://doi.org/10.1089/omi.2011.0118
25. Yu G, Wang LG, Yan GR, et al (2015) DOSE: an R/Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics 31:608–609. https://doi.org/10.1093/bioinformatics/btu684
26. Carlson M (2019) GO.db: A set of annotation maps describing the entire Gene Ontology. R package version 3.8.2.
27. Carlson M (2019) org.Hs.eg.db: Genome wide annotation for Human. R package version 3.8.2.
28. Yu G (2021) enrichplot: Visualization of Functional Enrichment Result. R package version 1.12.2.
29. Gonzalez MW, Kann MG (2012) Chapter 4: Protein Interactions and Disease. PLoS Comput Biol 8:e1002819. https://doi.org/10.1371/journal.pcbi.1002819
30. Shannon P, Markiel A, Ozier O, et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303
31. Szklarczyk D, Franceschini A, Wyder S, et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452. https://doi.org/10.1093/nar/gku1003
32. Bader GD, Hogue CW (2003) An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 2003 4:1 4:1–27. https://doi.org/10.1186/1471-2105-4-2
33. Freshour SL, Kiwala S, Cotto KC, et al (2021) Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts. Nucleic Acids Res 49:D1144–D1151. https://doi.org/10.1093/nar/gkaa1084
34. Tang Z, Kang B, Li C, et al (2019) GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res 47:W556–W560. https://doi.org/10.1093/nar/gkz430
35. Gu Z, Gu L, Eils R, et al (2014) circlize Implements and enhances circular visualization in R. Bioinformatics 30:2811–2812. https://doi.org/10.1093/bioinformatics/btu393
36. Nagy Á, Munkácsy G, Győrffy B (2021) Pancancer survival analysis of cancer hallmark genes. Scientific Rep 11:6047. https://doi.org/10.1038/s41598-021-84787-5
37. Chandrashekar DS, Bashel B, Balasubramanya S, et al (2017) UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia 19:649–658. https://doi.org/10.1016/j.neo.2017.05.002
38. Carrière C, Young AL, Gunn JR, et al (2009) Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem Biophys Res Commun 382:561. https://doi.org/10.1016/j.bbrc.2009.03.068
39. Kirkegård J, Mortensen FV, Cronin-Fenton D (2017) Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. Am J Gastroenterol 112:1366–1372. https://doi.org/10.1038/ajg.2017.218
40. Friedl P, Wolf K (2008) Tube travel: the role of proteases in individual and collective cancer cell invasion. Cancer Res 68:7247–7249. https://doi.org/10.1158/0008-5472.can-08-0784
41. Cox TR, Erler JT (2011) Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech 4:165–178. https://doi.org/10.1242/dmm.004077
42. Paszek MJ, Zahir N, Johnson KR, et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254. https://doi.org/10.1016/j.ccr.2005.08.010
43. Provenzano PP, Eliceiri KW, Campbell JM, et al (2006) Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 4:1–15. https://doi.org/10.1186/1741-7015-4-38
44. Fang M, Yuan J, Peng C, et al (2014) Collagen as a double-edged sword in tumor progression. Tumour Biol 35:2871–2882. https://doi.org/10.1007/s13277-013-1511-7
45. Xu S, Xu H, Wang W, et al (2019) The role of collagen in cancer: from bench to bedside. J Transl Med 17:1–22. https://doi.org/10.1186/s12967-019-2058-1
46. Kennedy AL, Morton JP, Manoharan I, et al (2011) Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis. Mol Cell 42:36–49. https://doi.org/10.1016/j.molcel.2011.02.020
47. Eser S, Reiff N, Messer M, et al (2013) Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23:406–420. https://doi.org/10.1016/j.ccr.2013.01.023
48. Baer R, Cintas C, Dufresne M, et al (2014) Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α. Genes Dev 28:2621–2635. https://doi.org/10.1101/gad.249409.114
49. Wang J, Svendsen A, Kmiecik J, et al (2011) Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma. PLoS One 6: e23062. https://doi.org/10.1371/journal.pone.0023062
50. Knelson EH, Nee JC, Blobe GC (2014) Heparan sulfate signaling in cancer. Trends Biochem Sci 39:277–288. https://doi.org/10.1016/j.tibs.2014.03.001
51. Kurihara T, Itoi T, Sofuni A, et al (2008) Detection of circulating tumor cells in patients with pancreatic cancer: a preliminary result. J Hepatobiliary Pancreat Surg 15:189–195. https://doi.org/10.1007/s00534-007-1250-5
52. Effenberger KE, Schroeder C, Hanssen A, et al (2018) Improved Risk Stratification by Circulating Tumor Cell Counts in Pancreatic Cancer. Clin Cancer Res 24:2844–2850. https://doi.org/10.1158/1078-0432.ccr-18-0120
53. Kita Y, Mimori K, Tanaka F, et al (2009) Clinical significance of LAMB3 and COL7A1 mRNA in esophageal squamous cell carcinoma. Eur J Surg Oncol 35:52–58. https://doi.org/10.1016/j.ejso.2008.01.025
54. Wu YH, Chang TH, Huang YF, et al (2014) COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer. Oncogene 33:3432–3440. https://doi.org/10.1038/onc.2013.307
55. Bonazzi VF, Nancarrow DJ, Stark MS, et al (2011) Cross-Platform Array Screening Identifies COL1A2, THBS1, TNFRSF10D and UCHL1 as Genes Frequently Silenced by Methylation in Melanoma. PLoS One 6:e26121. https://doi.org/10.1371/journal.pone.0026121
56. Hayashi M, Nomoto S, Hishida M, et al (2014) Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma. BMC Cancer 2014 14:1 14:1–10. https://doi.org/10.1186/1471-2407-14-108
57. Zhang Z, Fang C, Wang Y, et al (2018) COL1A1: A potential therapeutic target for colorectal cancer expressing wild-type or mutant KRAS. Int J Oncol 53:1869. https://doi.org/10.3892/ijo.2018.4536
58. Kim J, Bamlet WR, Oberg AL, et al (2017) Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med 9:eaah5583. https://doi.org/10.1126/scitranslmed.aah5583
59. Tian Q, Liu Y, Zhang Y, et al (2018) THBS2 is a biomarker for AJCC stages and a strong prognostic indicator in colorectal cancer. J BUON 23:1331–1336.