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TGF-\u03b2 is strongly expressed in both the epithelial and stromal compartments of PDAC, and dysregulation of TGF-\u03b2 signalling is a frequent molecular disturbance in PDAC progression and metastasis. In this study, we investigated whether blockade of TGF-\u03b2 signalling synergizes with nal-IRI\/5-FU\/LV, a chemotherapy regimen for malignant pancreatic cancer, in an orthotopic pancreatic tumour mouse model. Compared to nal-IRI\/5-FU\/LV treatment, combining nal-IRI\/5-FU\/LV with vactosertib, a TGF-\u03b2 signalling inhibitor, significantly improved long-term survival rates and effectively suppressed invasion to surrounding tissues. Through RNA-sequencing analysis, we identified that the combination treatment results in robust abrogation of tumour-promoting gene signatures and positive enrichment of tumour-suppressing and apoptotic gene signatures. Particularly, the expression of tumour-suppressing gene <jats:italic>Ccdc80<\/jats:italic> was induced by vactosertib and further induced by vactosertib in combination with nal-IRI\/5-FU\/LV. Ectopic expression of CCDC80 suppressed migration and colony formation concomitant with decreased expression of epithelial-to-mesenchymal transition (EMT) markers in pancreatic cancer cells. Collectively, these results indicate that combination treatment of vactosertib with nal-IRI\/5-FU\/LV improves overall survival rates in a mouse model of pancreatic cancer by suppressing invasion through CCDC80. Therefore, combination therapy of nal-IRI\/5-FU\/LV with vactosertib could provide clinical benefits to pancreatic cancer patients.<\/jats:p>","DOI":"10.1038\/s41598-020-59893-5","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T11:03:30Z","timestamp":1582110210000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Inhibition of TGF-\u03b2 signalling in combination with nal-IRI plus 5-Fluorouracil\/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models"],"prefix":"10.1038","volume":"10","author":[{"given":"Eunji","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujin","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Ooshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Pyo","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinah","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Sun","family":"Heo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyoung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haein","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Muk","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6210-4927","authenticated-orcid":false,"given":"Seok Hee","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon Oh","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Jin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,19]]},"reference":[{"key":"59893_CR1","first-page":"7","volume":"68","author":"RL Siegel","year":"2018","unstructured":"Siegel, R. 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