Gao, Z.-H. | bioRxiv Science

bioRxiv2024

The oncofetal protein IMP1 regulates the transcriptomic landscape to drive early events in pancreatic cancer progression and growth

Background & AimsPancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 12% - the lowest of all malignancies. This is partially due to late diagnosis, as early stages of the disease, including the process of acinar to ductal metaplasia (ADM) are not presently detectable. Insulin-like growth factor 2 mRNA binding protein (IMP)1 is an oncofetal protein implicated in cancer progression. Here, we aimed to determine its role in the early stages of PDAC development and in the maintenance of the malignant phenotype. MethodsIMP1 expression was analyzed in surgical PDAC specimens and in pancreatic tissue derived from KPC mice. Murine ductal organoids expressing the KrasG12D mutant were treated with the IMP1 inhibitor BTYNB and RNAseq performed. The function of IMP1 targets was analyzed in an ADM model and the effect of IMP1 silencing on the growth of PDAC cells was evaluated in vivo. ResultsWe found high expression of IMP1 in precancerous lesions of human and murine PDAC, but not in the normal pancreas. Blockade of IMP1 function impeded murine ADM and ductal organoid growth and profoundly altered the transcriptional landscape of the organoids, reducing the expression of cytokine-cytokine receptor interactors, cell adhesion and cell invasion mediators such as Card11, Gkn3, Il13ra2, Mmp9, and Vcam1. Gastrokine-3 and IL-13 in turn, enhanced the ADM process. Finally, IMP1 silencing in PDAC cells inhibited their metastatic outgrowth in mice. ConclusionsIMP1 is a master regulator of early events in PDAC progression and a potential biomarker and target for this disease.

cancer biology↗

bioRxiv2018

Verification of the phenylpropanoid pinoresinol biosynthetic pathway and its glycosides in Phomopsis sp. XP-8 using 13C stable isotope labeling and liquid chromatography coupled with time-of-flight mass spectrometry

Phomopsis sp. XP-8, an endophytic fungus from the bark of Tu-Chung (EucommiaulmoidesOliv), revealed the pinoresinol diglucoside (PDG) biosynthetic pathway after precursor feeding measurements and genomic annotation. To verify the pathway more accurately, [13C6]-labeled glucose and [13C6]-labeled phenylalanine were separately fed to the strain as sole substrates and [13C6]-labeled products were detected by ultra-high performance liquid chromatography-quantitative time of flight mass spectrometry. As results, [13C6]-labeled phenylalanine was found as [13C6]-cinnamylic acid and p-coumaric acid, and [13C12]-labeled pinoresinol revealed that the pinoresinol benzene ring came from phenylalanine via the phenylpropane pathway. [13C6]-Labeled cinnamylic acid and p-coumaric acid, [13C12]-labeled pinoresinol, [13C18]-labeled pinoresinol monoglucoside (PMG), and [13C18]-labeled PDG products were found when [13C6]-labeled glucose was used, demonstrating that the benzene ring and glucoside of PDG originated from glucose. It was also determined that PMG was not the direct precursor of PDG in the biosynthetic pathway. The study verified the occurrence of the plant-like phenylalanine and lignan biosynthetic pathway in fungi.\n\nImportanceVerify the phenylpropanoid-pinoresinol biosynthetic pathway and its glycosides in an endophytic fungi.

microbiology↗