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Pancreatic Neoplasms: HELP
Articles by Mats Ljungman
Based on 8 articles published since 2010
(Why 8 articles?)
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Between 2010 and 2020, Mats Ljungman wrote the following 8 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis. 2019

Wang, Lidong / Yang, Huibin / Zamperone, Andrea / Diolaiti, Daniel / Palmbos, Phillip L / Abel, Ethan V / Purohit, Vinee / Dolgalev, Igor / Rhim, Andrew D / Ljungman, Mats / Hadju, Christina H / Halbrook, Christopher J / Bar-Sagi, Dafna / di Magliano, Marina Pasca / Crawford, Howard C / Simeone, Diane M. ·Department of Surgery, New York University School of Medicine, New York, New York 10016, USA. · Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA. · Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. · Department of Pathology, New York University School of Medicine, New York, New York 10016, USA. · Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA. · Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. · Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. ·Genes Dev · Pubmed #31048544.

ABSTRACT: Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (

2 Article Synthesis and mechanistic studies of quinolin-chlorobenzothioate derivatives with proteasome inhibitory activity in pancreatic cancer cell lines. 2018

Hu, Shuai / Jin, Yi / Liu, Yanghan / Ljungman, Mats / Neamati, Nouri. ·Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, United States. · Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States; Key Laboratory of Medicinal Chemistry for Natural Resource, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, China. Electronic address: jinyi@ynu.edu.cn. · Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States. · Department of Radiation Oncology, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States. · Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address: neamati@umich.edu. ·Eur J Med Chem · Pubmed #30253345.

ABSTRACT: Inhibition of proteasome activity blocks the degradation of dysfunctional proteins and induces cancer cell death due to cellular stress. Thus, proteasome inhibitors represent an attractive class of anticancer agents, and bortezomib, carfilzomib and ixazomib have been FDA-approved to treat multiple myeloma. However, cancer cells acquire resistance to these inhibitors through point mutations in the proteasome catalytic subunit or induction of alternative compensatory mechanisms. In this study, we identified a quinolin-chlorobenzothioate, QCBT7, as a new proteasome inhibitor showing cytotoxicity in a panel of cancer cell lines. QCBT7 is a more stable derivative of quinoline-8-thiol that targets the regulatory subunit instead of the catalytic subunit of the proteasome. QCBT7 caused the accumulation of ubiquitylated proteins in the cancer cells, indicating its proteasome inhibitory activity. Additionally, QCBT7 increased the expression of a set of genes (PFKFB4, CHOP, HMOX1 and SLC7A11) at both nascent RNA and protein levels, similarly to the known proteasome inhibitors MG132 and ixazomib. Together, QCBT7 induces proteasome inhibition, hypoxic response, endoplasmic reticulum stress and glycolysis, finally leading to cell death. Importantly, we have identified PFKFB4 as a potential biomarker of proteasome inhibitors that can be used to monitor treatment response.

3 Article HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties. 2018

Abel, Ethan V / Goto, Masashi / Magnuson, Brian / Abraham, Saji / Ramanathan, Nikita / Hotaling, Emily / Alaniz, Anthony A / Kumar-Sinha, Chandan / Dziubinski, Michele L / Urs, Sumithra / Wang, Lidong / Shi, Jiaqi / Waghray, Meghna / Ljungman, Mats / Crawford, Howard C / Simeone, Diane M. ·Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, United States. · Translational Oncology Program, University of Michigan Health System, Ann Arbor, United States. · Department of Biostatistics, School of Public Health, University of Michigan Health System, Ann Arbor, United States. · Department of Pathology, University of Michigan Health System, Ann Arbor, United States. · Department of Surgery, New York University Langone Health, New York, United States. · Perlmutter Cancer Center, New York University Langone Health, New York, United states. · Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, United States. · Department of Pathology, New York University Langone Health, New York, United States. ·Elife · Pubmed #30074477.

ABSTRACT: The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of

4 Article Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma. 2018

Schofield, Heather K / Zeller, Jörg / Espinoza, Carlos / Halbrook, Christopher J / Del Vecchio, Annachiara / Magnuson, Brian / Fabo, Tania / Daylan, Ayse Ece Cali / Kovalenko, Ilya / Lee, Ho-Joon / Yan, Wei / Feng, Ying / Karim, Saadia A / Kremer, Daniel M / Kumar-Sinha, Chandan / Lyssiotis, Costas A / Ljungman, Mats / Morton, Jennifer P / Galbán, Stefanie / Fearon, Eric R / Pasca di Magliano, Marina. ·Department of Surgery. · Program in Cellular and Molecular Biology. · Medical Scientist Training Program. · Department of Internal Medicine. · Center for Molecular Imaging. · Department of Radiology. · Department of Molecular and Integrative Physiology, and. · Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. · Harvard University, Cambridge, Massachusetts, USA. · Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom. · Department of Pathology. · Comprehensive Cancer Center. · Department of Radiation Oncology. · Department of Environmental Health Sciences. · Department of Human Genetics, and. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. ·JCI Insight · Pubmed #29367463.

ABSTRACT: Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies.

5 Article Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma. 2018

Kuang, Yuting / Sechi, Mario / Nurra, Salvatore / Ljungman, Mats / Neamati, Nouri. ·Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States. · Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90033, United States. · Department of Chemistry and Pharmacy, University of Sassari , Via Vienna 2, 07100 Sassari, Italy. · Department of Radiation Oncology, University of Michigan , 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States. ·J Med Chem · Pubmed #29328656.

ABSTRACT: Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells. Furthermore, the QD compounds induced Nrf2-mediated oxidative stress and unfolded protein responses as demonstrated by dose-dependent increases in RNA synthesis of representative genes such as NQO1, HMOX1, DDIT3, and HSPA5. At higher concentrations, the QDs blocked mitochondrial function by inhibiting mtDNA transcription and downregulating the mtDNA-encoded OXPHOS enzymes. Importantly, treatments with QD325 were well tolerated in vivo and significantly delayed tumor growth in mice. Our study supports the development of QD325 as a new therapeutic in the treatment of PDAC.

6 Article PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. 2016

Roy, Nilotpal / Takeuchi, Kenneth K / Ruggeri, Jeanine M / Bailey, Peter / Chang, David / Li, Joey / Leonhardt, Laura / Puri, Sapna / Hoffman, Megan T / Gao, Shan / Halbrook, Christopher J / Song, Yan / Ljungman, Mats / Malik, Shivani / Wright, Christopher V E / Dawson, David W / Biankin, Andrew V / Hebrok, Matthias / Crawford, Howard C. ·Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Wolfson Wohl Cancer Research Center, University of Glasgow, Glasgow G61 1BD, Scotland. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA. · Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Medicine/ Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37240, USA. · Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. ·Genes Dev · Pubmed #28087712.

ABSTRACT: Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

7 Article ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis. 2015

Wang, Lidong / Yang, Huibin / Abel, Ethan V / Ney, Gina M / Palmbos, Phillip L / Bednar, Filip / Zhang, Yaqing / Leflein, Jacob / Waghray, Meghna / Owens, Scott / Wilkinson, John E / Prasad, Jayendra / Ljungman, Mats / Rhim, Andrew D / Pasca di Magliano, Marina / Simeone, Diane M. ·Department of Surgery, Translational Oncology Program. · Translational Oncology Program, Department of Pediatrics. · Translational Oncology Program, Department of Internal Medicine. · Department of Surgery. · Department of Pathology. · Department of Laboratory Animal Medicine. · Translational Oncology Program, Department of Radiation Oncology, Department of Molecular and Integrative Physiology. · Department of Internal Medicine. · Department of Surgery, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Surgery, Translational Oncology Program, Department of Molecular and Integrative Physiology, simeone@med.umich.edu. ·Genes Dev · Pubmed #25593307.

ABSTRACT: The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of β-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

8 Article ATDC/TRIM29 phosphorylation by ATM/MAPKAP kinase 2 mediates radioresistance in pancreatic cancer cells. 2014

Wang, Lidong / Yang, Huibin / Palmbos, Phillip L / Ney, Gina / Detzler, Taylor Ann / Coleman, Dawn / Leflein, Jacob / Davis, Mary / Zhang, Min / Tang, Wenhua / Hicks, J Kevin / Helchowski, Corey M / Prasad, Jayendra / Lawrence, Theodore S / Xu, Liang / Yu, Xiaochun / Canman, Christine E / Ljungman, Mats / Simeone, Diane M. ·Authors' Affiliations: Departments of Surgery, Radiation Oncology, Pharmacology, Internal Medicine and Molecular and Integrative Physiology, Translational Oncology Program, and Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan. ·Cancer Res · Pubmed #24469230.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by therapeutic resistance for which the basis is poorly understood. Here, we report that the DNA and p53-binding protein ATDC/TRIM29, which is highly expressed in PDAC, plays a critical role in DNA damage signaling and radioresistance in pancreatic cancer cells. Ataxia-telangiectasia group D-associated gene (ATDC) mediated resistance to ionizing radiation in vitro and in vivo in mouse xenograft assays. ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC. Our results identify a DNA repair pathway leading from MK2 and ATM to ATDC, suggesting its candidacy as a therapeutic target to radiosensitize PDAC and improve the efficacy of DNA-damaging treatment.