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Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism.
Krah NM, Narayanan SM, Yugawa DE, Straley JA, Wright CVE, MacDonald RJ, Murtaugh LC
(2019) Dev Cell 50: 744-754.e4
MeSH Terms: Acinar Cells, Animals, Carcinogenesis, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Clone Cells, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Inflammation, Mice, Pancreatic Neoplasms, Pancreatitis, Phenotype, Proto-Oncogene Proteins p21(ras), Signal Transduction, Transcription Factors
Show Abstract · Added September 3, 2019
Activating mutations in Kras are nearly ubiquitous in human pancreatic cancer and initiate precancerous pancreatic intraepithelial neoplasia (PanINs) when induced in mouse acinar cells. PanINs normally take months to form but are accelerated by deletion of acinar cell differentiation factors such as Ptf1a, suggesting that loss of cell identity is rate limiting for pancreatic tumor initiation. Using a genetic mouse model that allows for independent control of oncogenic Kras and Ptf1a expression, we demonstrate that sustained Ptf1a is sufficient to prevent Kras-driven tumorigenesis, even in the presence of tumor-promoting inflammation. Furthermore, reintroducing Ptf1a into established PanINs reverts them to quiescent acinar cells in vivo. Similarly, Ptf1a re-expression in human pancreatic cancer cells inhibits their growth and colony-forming ability. Our results suggest that reactivation of an endogenous differentiation program can prevent and reverse oncogene-driven transformation in cells harboring tumor-driving mutations, introducing a potential paradigm for solid tumor prevention and treatment.
Copyright © 2019 Elsevier Inc. All rights reserved.
1 Communities
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18 MeSH Terms
Differential Cell Susceptibilities to Kras in the Setting of Obstructive Chronic Pancreatitis.
Shi C, Pan FC, Kim JN, Washington MK, Padmanabhan C, Meyer CT, Kopp JL, Sander M, Gannon M, Beauchamp RD, Wright CV, Means AL
(2019) Cell Mol Gastroenterol Hepatol 8: 579-594
MeSH Terms: Acinar Cells, Animals, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, Disease Models, Animal, Genes, ras, Metaplasia, Mice, Mutation, Pancreatic Neoplasms, Pancreatitis, Chronic, Precancerous Conditions, Proto-Oncogene Proteins p21(ras), Signal Transduction
Show Abstract · Added August 6, 2019
BACKGROUND & AIMS - Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known.
METHODS - We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells.
RESULTS - Although Kras expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant duct cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time.
CONCLUSIONS - One mechanism by which tissues may be susceptible or resistant to KRAS-initiated tumorigenesis is whether they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
2 Communities
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15 MeSH Terms
Active Kras Expression in Gastric Isthmal Progenitor Cells Induces Foveolar Hyperplasia but Not Metaplasia.
Choi E, Means AL, Coffey RJ, Goldenring JR
(2019) Cell Mol Gastroenterol Hepatol 7: 251-253.e1
MeSH Terms: Animals, Biomarkers, Humans, Hyperplasia, Metaplasia, Mice, Proto-Oncogene Proteins p21(ras), Stem Cells, Stomach
Added February 7, 2019
1 Communities
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9 MeSH Terms
Small Cell Lung Cancer Transformation as a Mechanism of Resistance to PD-1 Therapy in KRAS-Mutant Lung Adenocarcinoma: A Report of Two Cases.
Iams WT, Beckermann KE, Almodovar K, Hernandez J, Vnencak-Jones C, Lim LP, Raymond CK, Horn L, Lovly CM
(2019) J Thorac Oncol 14: e45-e48
MeSH Terms: Adenocarcinoma of Lung, Aged, Antineoplastic Agents, Immunological, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Female, Humans, Lung Neoplasms, Mutation, Prognosis, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins p21(ras), Small Cell Lung Carcinoma
Added September 10, 2020
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MeSH Terms
Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.
Liu Y, Sethi NS, Hinoue T, Schneider BG, Cherniack AD, Sanchez-Vega F, Seoane JA, Farshidfar F, Bowlby R, Islam M, Kim J, Chatila W, Akbani R, Kanchi RS, Rabkin CS, Willis JE, Wang KK, McCall SJ, Mishra L, Ojesina AI, Bullman S, Pedamallu CS, Lazar AJ, Sakai R, Cancer Genome Atlas Research Network, Thorsson V, Bass AJ, Laird PW
(2018) Cancer Cell 33: 721-735.e8
MeSH Terms: Adenocarcinoma, Aneuploidy, Chromosomal Instability, DNA Methylation, DNA Polymerase II, Epigenesis, Genetic, Female, Gastrointestinal Neoplasms, Gene Regulatory Networks, Heterogeneous-Nuclear Ribonucleoproteins, Humans, Male, Microsatellite Instability, MutL Protein Homolog 1, Mutation, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins p21(ras), SOX9 Transcription Factor
Show Abstract · Added October 30, 2019
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice.
Kimura Y, Fukuda A, Ogawa S, Maruno T, Takada Y, Tsuda M, Hiramatsu Y, Araki O, Nagao M, Yoshikawa T, Ikuta K, Yoshioka T, Wang Z, Akiyama H, Wright CV, Takaori K, Uemoto S, Chiba T, Seno H
(2018) Gastroenterology 155: 194-209.e2
MeSH Terms: Adenocarcinoma in Situ, Animals, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Culture Techniques, Cell Differentiation, DNA-Binding Proteins, Mice, Nuclear Proteins, Pancreatic Ducts, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), SOX9 Transcription Factor
Show Abstract · Added April 3, 2018
BACKGROUND & AIMS - The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice.
METHODS - We performed studies with Ptf1a-Cre;Kras mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;Kras;Arid1a mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a-Cre;Kras; Brg1mice). Pancreatic ductal cells (PDCs) were isolated from Arid1a mice and from Arid1a;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry.
RESULTS - Ptf1a-Cre;Kras mice developed PanINs, whereas Ptf1a-Cre;Kras;Arid1a mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6.
CONCLUSIONS - ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
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13 MeSH Terms
IκB Kinase α Is Required for Development and Progression of -Mutant Lung Adenocarcinoma.
Vreka M, Lilis I, Papageorgopoulou M, Giotopoulou GA, Lianou M, Giopanou I, Kanellakis NI, Spella M, Agalioti T, Armenis V, Goldmann T, Marwitz S, Yull FE, Blackwell TS, Pasparakis M, Marazioti A, Stathopoulos GT
(2018) Cancer Res 78: 2939-2951
MeSH Terms: A549 Cells, Adenocarcinoma of Lung, Animals, Cell Line, Cell Line, Tumor, Disease Progression, HEK293 Cells, Humans, I-kappa B Kinase, Lung Neoplasms, Mice, Mice, Inbred C57BL, NF-kappa B, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins p21(ras), Signal Transduction
Show Abstract · Added March 31, 2020
Although oncogenic activation of NFκB has been identified in various tumors, the NFκB-activating kinases (inhibitor of NFκB kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in -mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic Using NFκB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NFκB during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of B, IκBβ, and IKKα in tumor-initiated cells. IKKα was a cardinal tumor promoter in chemical and genetic -mutant lung adenocarcinoma, and respiratory epithelial IKKα-deficient mice were markedly protected from the disease. IKKα specifically cooperated with mutant for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage and IKKα was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against -mutant lung adenocarcinoma compared with a specific IKKβ inhibitor. These results demonstrate an actionable requirement for IKKα in -mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease. These findings report a novel requirement for IKKα in mutant lung tumor formation, with potential therapeutic applications. .
©2018 American Association for Cancer Research.
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Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma.
Cancer Genome Atlas Research Network. Electronic address: andrew_aguirre@dfci.harvard.edu, Cancer Genome Atlas Research Network
(2017) Cancer Cell 32: 185-203.e13
MeSH Terms: Carcinoma, Pancreatic Ductal, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Humans, Mutation, Pancreatic Neoplasms, Proteome, Proto-Oncogene Proteins p21(ras), Transcriptome
Show Abstract · Added October 30, 2019
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells.
Pickup MW, Owens P, Gorska AE, Chytil A, Ye F, Shi C, Weaver VM, Kalluri R, Moses HL, Novitskiy SV
(2017) Cancer Immunol Res 5: 718-729
MeSH Terms: Adenocarcinoma, Animals, Carcinoma, Pancreatic Ductal, Cell Proliferation, Disease Models, Animal, Disease Progression, Gene Expression Regulation, Neoplastic, Granulocyte Colony-Stimulating Factor, Humans, Interferon-Stimulated Gene Factor 3, gamma Subunit, Mice, Mice, Knockout, Proto-Oncogene Proteins p21(ras), Signal Transduction, T-Lymphocytes, Transforming Growth Factor beta
Show Abstract · Added July 17, 2019
The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48), we discovered an effect of TGFβ signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, and IL1b from CD11b cells. Deletion of in PDAC cells or use of a G-CSF-blocking antibody decreased tumor growth. Anti-G-CSF treatment in combination with the DNA synthesis inhibitor gemcitabine reduced tumor size, increased the number of infiltrating T cells, and decreased the number of Ly6G cells more effectively than gemcitabine alone. Human analysis of human datasets from The Cancer Genome Atlas and tissue microarrays correlated with observations from our mouse model experiments, especially in patients with grade 1, stage II disease. We propose that in aggressive PDAC, elevated G-CSF contributes to tumor progression through promoting increases in infiltration of neutrophil-like cells with high immunosuppressive activity. Such a mechanism provides an avenue for a neoadjuvant therapeutic approach for this devastating disease. .
©2017 American Association for Cancer Research.
1 Communities
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MeSH Terms
IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling.
Wang YA, Sun Y, Palmer J, Solomides C, Huang LC, Shyr Y, Dicker AP, Lu B
(2017) Mol Cancer Res 15: 896-904
MeSH Terms: Animals, Apoptosis, Biomarkers, Tumor, Carcinogenesis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Cisplatin, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Mice, Mice, Knockout, Proto-Oncogene Proteins p21(ras)
Show Abstract · Added April 18, 2017
Insulin-like growth factor binding protein 3 (IGFBP3) modulates cell growth through IGF-dependent and -independent mechanisms. Reports suggest that the serum levels of IGFBP3 are associated with various cancers and that IGFBP3 expression is significantly decreased in cisplatin (CDDP)-resistant lung cancer cells. Based on these findings, we investigated whether deficiency accelerates mouse lung tumorigenesis and if expression of IGFBP3 enhances CDDP response by focusing on the IGF1 signaling cascade. To this end, an -null mouse model was generated in combination with to compare the tumor burden. Then, IGF-dependent signaling was assessed after expressing wild-type or a mutant IGFBP3 without IGF binding capacity in non-small cell lung cancer (NSCLC) cells. Finally, the treatment response to CDDP chemotherapy was evaluated under conditions of IGFBP3 overexpression. -null mice had increased lung tumor burden (>2-fold) and only half of human lung cancer cells survived after expression of IGFBP3, which corresponded to increased cleaved caspase-3 (10-fold), inactivation of IGF1 and MAPK signaling. In addition, overexpression of IGFBP3 increased susceptibility to CDDP treatment in lung cancer cells. These results, for the first time, demonstrate that IGFBP3 mediates lung cancer progression in a mouse model. Furthermore, overexpression of IGFBP3 induced apoptosis and enhanced cisplatin response and confirmed that the suppression is in part by blocking IGF1 signaling. These findings reveal that IGFBP3 is effective in lung cancer cells with high IGF1 signaling activity and imply that relevant biomarkers are essential in selecting lung cancer patients for IGF1-targeted therapy. .
©2017 American Association for Cancer Research.
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16 MeSH Terms