Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Roe, Jae Seok; Hwang, Chang-Il; Somerville, Tim D.D.; Milazzo, Joseph P.; Lee, Eun Jung; Silva, Brandon Da; Maiorino, Laura; Tiriac, Hervé; Young, Chloe; Miyabayashi, Koji; Filippini, Dea; Creighton, Brianna; Burkhart, Richard A.; Buscaglia, Jonathan M.; Kim, Edward; Grem, Jean L.; Lazenby, Audrey J.; Grunkemeyer, James A.; Hollingsworth, Michael A.; Grandgenett, Paul M.; Egeblad, Mikala; Park, Young-Kyu; Tuveson, David A.; Vakoc, Christopher R.

doi:10.1016/j.cell.2017.07.007

Cited by 388 publications

(427 citation statements)

References 61 publications

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“…PDAC metastases from distant sites were dependent on the oxidative pentose phosphate pathway for the maintenance of their malignant gene expression programs. Roe et al [34] also used a mouse PDAC model and found that the transition to a metastatic state was accompanied by massive FoxA1-driven enhancer activation. The newly activated genes rendered cells more invasive, and they assumed a cell fate resembling that of the embryonic foregut endoderm.…”

Section: Advantages Provided For Cancer Research By Cancer Cell Repromentioning

confidence: 99%

“…The authors provided evidence that this tumorigenesis was caused by epigenetic reprogramming, as the oncogenic enhancers were reactivated in the cancer cell counterparts. Furthermore, recent works have illustrated an important role of the epigenetic reprogramming of chromatin modifications in the evolution of cancer metastasis [32–34]. These articles emphasize the fact that reprogramming can lead to the formation of tumor-initiating cells that acquire stem cell-like phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…These articles emphasize the fact that reprogramming can lead to the formation of tumor-initiating cells that acquire stem cell-like phenotypes. Interestingly, the three-dimensional (3D) tumor sphere-forming assay is a unique model of cancer that can be used to investigate malignant heterogeneity in tumorigenesis [34, 35]. Therefore, the tumorigenic potential of the use of reprogrammed stem cells for clinical applications should be recognized and new approaches for safe stem cell therapy should be developed.…”

Section: Introductionmentioning

confidence: 99%

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Potential application of cell reprogramming techniques for cancer research

Saito

Lin

Nakamura

et al. 2018

Cell. Mol. Life Sci.

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The ability to control the transition from an undifferentiated stem cell to a specific cell fate is one of the key techniques that are required for the application of interventional technologies to regenerative medicine and the treatment of tumors and metastases and of neurodegenerative diseases. Reprogramming technologies, which include somatic cell nuclear transfer, induced pluripotent stem cells, and the direct reprogramming of specific cell lineages, have the potential to alter cell plasticity in translational medicine for cancer treatment. The characterization of cancer stem cells (CSCs), the identification of oncogene and tumor suppressor genes for CSCs, and the epigenetic study of CSCs and their microenvironments are important topics. This review summarizes the application of cell reprogramming technologies to cancer modeling and treatment and discusses possible obstacles, such as genetic and epigenetic alterations in cancer cells, as well as the strategies that can be used to overcome these obstacles to cancer research.

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Section: Advantages Provided For Cancer Research By Cancer Cell Repromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potential application of cell reprogramming techniques for cancer research

Saito

Lin

Nakamura

et al. 2018

Cell. Mol. Life Sci.

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“…Pancreatic cancer is a lethal tumor characterized by early metastasis and a high recurrence rate, with a dismal 5-year survival rate of less than 8% [1][2][3]. Unlike many other cancers, patients remain almost symptomless in the early stage of this disease.…”

Section: Introductionmentioning

confidence: 99%

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling

Chen

Jiang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism. Methods: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2’-7’-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer. Results: SFN can inhibit pancreatic cancer cell growth， promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group. Conclusion: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer.

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“…These include the metastasis enhancer FOXA1 and the putative tumor suppressor FOXO6 . Interestingly, the known role of FOXA1 in the metastatic transition of pancreas cancer, originally identified in the KPC animal model used in this study, and the tumor suppressor functions of FOXO6 in lung cancer cells provide biologically plausible links to the anti-metastatic phenotype of metarrestin [35–37]. …”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

Vilimas

Wang

Patnaik

et al. 2018

Cancer Chemother Pharmacol

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PurposeMetarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers.MethodsPK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice.ResultsMetarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors.ConclusionsMetarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.Electronic supplementary materialThe online version of this article (10.1007/s00280-018-3699-0) contains supplementary material, which is available to authorized users.

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Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Cited by 388 publications

References 61 publications

Potential application of cell reprogramming techniques for cancer research

Potential application of cell reprogramming techniques for cancer research

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling

Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

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