EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Scientists characterized the mechanistic and functional implications of the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) in controlling pancreatic ductal adenocarcinoma plasticity, dedifferentiation, and molecular subtype identity.
[Cancer Research]
Patil, S., Steuber, B., Kopp, W., Kari, V., Urbach, L., Wang, X., Küffer, S., Bohnenberger, H., Spyropoulou, D., Zhang, Z., Versemann, L., Bösherz, M. S., Brunner, M., Gaedcke, J., Ströbel, P., Zhang, J.-S., Neesse, A., Ellenrieder, V., Singh, S. K., … Hessmann, E. (2020). EZH2 regulates pancreatic cancer subtype identity and tumor progression via transcriptional repression of GATA6. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-20-0672 Cite
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RET Isoforms Contribute Differentially to Invasive Processes in Pancreatic Ductal Adenocarcinoma

The authors generated total RET and isoform-specific knockdown pancreatic ductal adenocarcinoma (PDAC) cell lines and assessed the contributions of RET isoforms to PDAC invasive spread. They showed that RET activity induced cell polarization and actin remodeling through activation of CDC42 and RHOA GTPases to promote directional motility in PDAC cells.
[Oncogene]
Lian, E. Y., Hyndman, B. D., Moodley, S., Maritan, S. M., & Mulligan, L. M. (2020). RET isoforms contribute differentially to invasive processes in pancreatic ductal adenocarcinoma. Oncogene, 1–18. https://doi.org/10.1038/s41388-020-01448-z Cite
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MYEOV Increases HES1 Expression and Promotes Pancreatic Cancer Progression by Enhancing SOX9 Transactivity

Researchers provided evidence of essential roles of myeloma overexpressed (MYEOV) in the development and progression of pancreatic ductal adenocarcinoma. In tumor specimens derived from pancreatic cancer patients, MYEOV was overexpressed and associated with poor prognosis.
[Oncogene]
Liang, E., Lu, Y., Shi, Y., Zhou, Q., & Zhi, F. (2020). MYEOV increases HES1 expression and promotes pancreatic cancer progression by enhancing SOX9 transactivity. Oncogene, 1–14. https://doi.org/10.1038/s41388-020-01443-4 Cite
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Multidrug Transporter MRP4/ABCC4 as a Key Determinant of Pancreatic Cancer Aggressiveness

Scientists determined the role of MRP4 in pancreatic ductal adenocarcinoma (PDAC) tumor aggressiveness. Bioinformatic studies revealed that PDAC samples showed higher MRP4 transcript levels compared to normal adjacent pancreatic tissue and circulating tumor cells expressed higher levels of MRP4 than primary tumors.
[Scientific Reports]
Sahores, A., Carozzo, A., May, M., Gómez, N., Di Siervi, N., De Sousa Serro, M., Yaneff, A., Rodríguez-González, A., Abba, M., Shayo, C., & Davio, C. (2020). Multidrug transporter MRP4/ABCC4 as a key determinant of pancreatic cancer aggressiveness. Scientific Reports, 10(1), 14217. https://doi.org/10.1038/s41598-020-71181-w Cite
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TET1 Downregulates Epithelial-Mesenchymal Transition and Chemoresistance in PDAC by Demethylating CHL1 to Inhibit the Hedgehog Signaling Pathway

In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 was able to suppress epithelial-mesenchymal transition and sensitize pancreatic ductal adenocarcinoma cells to 5FU and gemcitabine. RNA-seq, whole genome bisulfite sequencing and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promoted the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway.
[Oncogene]
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Metformin Inhibits Pancreatic Cancer Metastasis Caused by SMAD4 Deficiency and Consequent HNF4G Upregulation

The authors found that metformin suppressed HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibited in vitro invasion and in vivo metastasis of pancreatic ductal adenocarcinoma cells with SMAD4 deficiency.
[Protein & Cell]
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Pancreatic Circulating Tumor Cell Profiling Identifies LIN28B as a Metastasis Driver and Drug Target

Using the circulating tumor cell (CTC)-iChip to purify CTCs from pancreatic ductal adenocarcinoma patients for RNA-seq characterization, scientists identified three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic.
[Nature Communications]
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WD Repeat-Containing Protein 1 Maintains β-Catenin Activity to Promote Pancreatic Cancer Aggressiveness

Scientists identified several previous functional unknown proteins implicated in the progression of pancreatic ductal adenocarcinoma (PDAC), and provided new insight into the oncogenic roles of WD repeat-containing protein 1 in PDAC development.
[British Journal of Cancer]
Li, H., Liu, X., Jiang, S., Zhou, X., Yao, L., Di, Y., Jiang, Y., Gu, J., Mao, Y., Li, J., Jin, C., Yang, P., & Fu, D. (2020). WD repeat-containing protein 1 maintains β-Catenin activity to promote pancreatic cancer aggressiveness. British Journal of Cancer, 1–12. https://doi.org/10.1038/s41416-020-0929-0 Cite
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High Expression of AMAP1, An ARF6 Effector, Is Associated with Elevated Levels of PD-L1 and Fibrosis of Pancreatic Cancer

With an aim to understand whether the ARF6-AMAP1 pathway was critically involved in the elevated levels of PD-L1 and fibrosis of pancreatic ductal carcinoma, investigators analyzed the relationship between AMAP1 and these malignant phenotypes.
[Cell Communication and Signaling]
Tsutaho, A., Hashimoto, A., Hashimoto, S., Hata, S., Kachi, S., Hirano, S., & Sabe, H. (2020). High expression of AMAP1, an ARF6 effector, is associated with elevated levels of PD-L1 and fibrosis of pancreatic cancer. Cell Communication and Signaling, 18(1), 101. https://doi.org/10.1186/s12964-020-00608-8 Cite
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CD200 Promotes Immunosuppression in the Pancreatic Tumor Microenvironment

Myeloid-derived suppressor cells isolated from patients with pancreatic ductal adenocarcinoma expressed elevated levels of the CD200 receptor.
[Journal For ImmunoTherapy of Cancer]
Choueiry, F., Torok, M., Shakya, R., Agrawal, K., Deems, A., Benner, B., Hinton, A., Shaffer, J., Blaser, B. W., Noonan, A. M., Williams, T. M., Dillhoff, M., Conwell, D. L., Hart, P. A., Cruz-Monserrate, Z., Bai, X.-F., Iii, W. E. C., & Mace, T. A. (2020). CD200 promotes immunosuppression in the pancreatic tumor microenvironment. Journal for ImmunoTherapy of Cancer, 8(1), e000189. https://doi.org/10.1136/jitc-2019-000189 Cite
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VentX Expression in Tumor Associated Macrophages Promotes Phagocytosis and Immunity against Pancreatic Cancers

Investigators found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, is significantly decreased in the ancreatic ductal adenocarcinoma (PDA)-tumor associated macrophages (TAMs). They demonstrated that VentX was required for phagocytosis and that restoration of VentX expression in PDA-TAMs promoted phagocytosis through regulating the signaling cascades involved in the process.
[JCI Insight]
Le, Y., Gao, H., Richards, W. G., Zhao, L., Bleday, R., Clancy, T., & Zhu, Z. (2020). VentX expression in tumor associated macrophages promotes phagocytosis and immunity against pancreatic cancers. JCI Insight. https://doi.org/10.1172/jci.insight.137088 Cite
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