Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models

  • Sci Rep. 2020 Feb 19;10(1):2935. doi: 10.1038/s41598-020-59893-5.
Eunji Hong  1  2 ,  Sujin Park  3 ,  Akira Ooshima  1 ,  Chang Pyo Hong  4 ,  Jinah Park  1 ,  Jin Sun Heo  1 ,  Siyoung Lee  1 ,  Haein An  1 ,  Jin Muk Kang  1 ,  Seok Hee Park  2 ,  Joon Oh Park  5 ,  Seong-Jin Kim  1  6  4  7
Affiliations
  • 1. Precision Medicine Research Center, Advanced Institute of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, 16229, Republic of Korea.
  • 2. Department of Biological Science, Sungkyunkwan University, Suwon, 16419, Gyeonggi-do, Republic of Korea.
  • 3. Precision Medicine Research Center, Advanced Institute of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, 16229, Republic of Korea. [email protected].
  • 4. TheragenEtex Bio Institute, Suwon, Gyeonggi-do, 16229, Republic of Korea.
  • 5. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • 6. Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Gyeonggi-do, 16229, Republic of Korea.
  • 7. Medpacto Inc., Seoul, Republic of Korea.
PMID: 32076068 DOI: 10.1038/s41598-020-59893-5
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies. TGF-β is strongly expressed in both the epithelial and stromal compartments of PDAC, and dysregulation of TGF-β signalling is a frequent molecular disturbance in PDAC progression and metastasis. In this study, we investigated whether blockade of TGF-β 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-β 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 Ccdc80 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.

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