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

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 tumoursuppressing 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.Pancreatic cancer is one of the leading causes of cancer-related mortality in the world. The 5-year relative survival rate of pancreatic ductal adenocarcinoma (PDAC) patients was only 8% for all stages combined data in 2018 1 . Although 5-year relative survival rates in other cancer types have steadily increased over the years, improvement in pancreatic cancer is very slow because patients with pancreatic cancer are often diagnosed at advanced stages due to absence of noticeable symptoms in the early stages 2,3 . Moreover, control of pancreatic cancer is difficult owing to its aggressiveness, distal metastasis, resistance to most common treatments, and genetic and epigenetic alterations 4-6 .The pancreatic cancer treatment paradigm has improved in the last 20 years. In clinical trials in the 1970s, 5-fluorouracil (5-FU) was used after resection 7 . Nowadays, the combination treatments such as FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil (5-FU), and leucovorin (LV)) and gemcitabine plus nab-paclitaxel are the novel chemotherapy regimens used for patients with metastatic pancreatic adenocarcinoma (mPAC), displaying significantly better patient outcomes compared to the commonly used gemcitabine and providing the chance for salvage chemotherapy [8][9][10] . Nanoliposomal irinotecan (nal-IRI) has different pharmacokinetic properties from irinotecan owing to the outer PEGylated liposomes encapsulating the irinotecan sucrosofate ...

Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2

“…However, the mechanism by which NP treatment inhibits CCDC80 expression requires further study. Recent study suggested that activation of TGF-β signaling could inhibit the expression of CCDC80 (Hong et al, 2020), which suggested that NP might influence the expression of CCDC80 by activating other signaling pathways. Additionally, our data revealed that NP treatment activated ERK1/2, even when co-treated with CCDC80 overexpression.…”

Magnolol Suppresses Pancreatic Cancer Development In Vivo and In Vitro via Negatively Regulating TGF-β/Smad Signaling

“…Conversely, TGF-β signaling accelerates tumor progression in advanced-stage pancreatic cancer by inducing EMT, metastasis, invasion, migration, and immune evasion ( 27 ). In fact, the contribution of TGFβ to metastases has been well proven in pancreatic cancer ( 28 , 29 ). Zhang et al.…”

Epithelial-Mesenchymal Transition and Its Regulation Mechanisms in Pancreatic Cancer

“…Nonetheless, EMT has been reported to contribute to pancreatic cancer cells' drug resistance (14) as well as relate strongly to poor prognosis of PDAC (15). Moreover, recent evidence has been lent to genetic, molecular, and biochemical mechanisms mediating the EMT process in progression and metastasis of pancreatic cancer (16,17), which strengthens the view of EMT as a cancer hallmark. While prior reviews have largely focused on molecular (e.g., Elaskalani et al (18), Safa (19)) or biochemical mechanisms (e.g., inflammation, Khalafalla and Khan (20), Wang et al (21)) underlying the EMT process in pancreatic cancer, this essay depicts recent evidence for the role of EMT-regulating mechanisms in pancreatic cancer in terms of genetic, molecular, and biochemical aspects.…”

“…An extension of this research stream should be to investigate the role of other tumor suppressing genes such as PTEN and CDKN2A (46) as genetic regulating factors underlying EMT process in proliferation of pancreatic cancer. In addition, the suppressing role of CCDC80 in EMT processes should be examined in other carcinoma types than pancreatic (16), hepatocellular (47), and lung carcinoma (48).…”