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Histone deacetylase 3 controls a transcriptional network required for B cell maturation.
Stengel KR, Bhaskara S, Wang J, Liu Q, Ellis JD, Sampathi S, Hiebert SW
(2019) Nucleic Acids Res 47: 10612-10627
MeSH Terms: Animals, Antigens, CD19, B-Lymphocytes, Base Sequence, Cell Differentiation, Gene Expression Regulation, Gene Regulatory Networks, Histone Deacetylase Inhibitors, Histone Deacetylases, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred C57BL, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Transcription, Genetic, Up-Regulation
Show Abstract · Added October 25, 2019
Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3-/- germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3-/- germinal centers were a result of direct effects of Hdac3 deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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18 MeSH Terms
Bcl2-Expressing Quiescent Type B Neural Stem Cells in the Ventricular-Subventricular Zone Are Resistant to Concurrent Temozolomide/X-Irradiation.
Cameron BD, Traver G, Roland JT, Brockman AA, Dean D, Johnson L, Boyd K, Ihrie RA, Freeman ML
(2019) Stem Cells 37: 1629-1639
MeSH Terms: Animals, Antineoplastic Agents, Alkylating, Apoptosis, Chemoradiotherapy, DNA Breaks, Double-Stranded, DNA Repair, Disease Models, Animal, Drug Resistance, Female, Glioblastoma, Lateral Ventricles, Male, Mice, Mice, Inbred C57BL, Neural Stem Cells, Neurogenesis, Proto-Oncogene Proteins c-bcl-2, Temozolomide, X-Ray Therapy
Show Abstract · Added March 3, 2020
The ventricular-subventricular zone (V-SVZ) of the mammalian brain is a site of adult neurogenesis. Within the V-SVZ reside type B neural stem cells (NSCs) and type A neuroblasts. The V-SVZ is also a primary site for very aggressive glioblastoma (GBM). Standard-of-care therapy for GBM consists of safe maximum resection, concurrent temozolomide (TMZ), and X-irradiation (XRT), followed by adjuvant TMZ therapy. The question of how this therapy impacts neurogenesis is not well understood and is of fundamental importance as normal tissue tolerance is a limiting factor. Here, we studied the effects of concurrent TMZ/XRT followed by adjuvant TMZ on type B stem cells and type A neuroblasts of the V-SVZ in C57BL/6 mice. We found that chemoradiation induced an apoptotic response in type A neuroblasts, as marked by cleavage of caspase 3, but not in NSCs, and that A cells within the V-SVZ were repopulated given sufficient recovery time. 53BP1 foci formation and resolution was used to assess the repair of DNA double-strand breaks. Remarkably, the repair was the same in type B and type A cells. While Bax expression was the same for type A or B cells, antiapoptotic Bcl2 and Mcl1 expression was significantly greater in NSCs. Thus, the resistance of type B NSCs to TMZ/XRT appears to be due, in part, to high basal expression of antiapoptotic proteins compared with type A cells. This preclinical research, demonstrating that murine NSCs residing in the V-SVZ are tolerant of standard chemoradiation therapy, supports a dose escalation strategy for treatment of GBM. Stem Cells 2019;37:1629-1639.
© 2019 The Authors. Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2019.
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19 MeSH Terms
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.
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18 MeSH Terms
MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.
Vilgelm AE, Saleh N, Shattuck-Brandt R, Riemenschneider K, Slesur L, Chen SC, Johnson CA, Yang J, Blevins A, Yan C, Johnson DB, Al-Rohil RN, Halilovic E, Kauffmann RM, Kelley M, Ayers GD, Richmond A
(2019) Sci Transl Med 11:
MeSH Terms: Analysis of Variance, Animals, Blotting, Western, Cell Cycle, Cell Survival, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p21, DNA Replication, Dimethyl Sulfoxide, Humans, Immunoprecipitation, MCF-7 Cells, Melanoma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Proteomics, Proto-Oncogene Proteins c-mdm2, Radioimmunoprecipitation Assay
Show Abstract · Added September 27, 2019
Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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21 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.
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15 MeSH Terms
Identification of Targetable Recurrent MAP3K8 Rearrangements in Melanomas Lacking Known Driver Mutations.
Lehmann BD, Shaver TM, Johnson DB, Li Z, Gonzalez-Ericsson PI, Sánchez V, Shyr Y, Sanders ME, Pietenpol JA
(2019) Mol Cancer Res 17: 1842-1853
MeSH Terms: Algorithms, Cell Line, Tumor, Databases, Genetic, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Kinase Kinases, Male, Melanoma, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Sequence Analysis, RNA, Sequence Deletion, Survival Analysis, Translocation, Genetic, Up-Regulation
Show Abstract · Added March 30, 2020
Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma, we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in more than 15% of tumors without known driver mutations (, and ). Using an independent tumor set, we validated a similar rearrangement frequency by FISH. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells result in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma, and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements. IMPLICATIONS: This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.
©2019 American Association for Cancer Research.
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17 MeSH Terms
Akt Signaling in Macrophage Polarization, Survival, and Atherosclerosis.
Linton MF, Moslehi JJ, Babaev VR
(2019) Int J Mol Sci 20:
MeSH Terms: Animals, Apoptosis, Atherosclerosis, Blood Cells, Cell Survival, Humans, Macrophage Activation, Macrophages, Phosphatidylinositol 3-Kinases, Protein Isoforms, Proto-Oncogene Proteins c-akt, Signal Transduction
Show Abstract · Added November 12, 2019
The PI3K/Akt pathway plays a crucial role in the survival, proliferation, and migration of macrophages, which may impact the development of atherosclerosis. Changes in Akt isoforms or modulation of the Akt activity levels in macrophages significantly affect their polarization phenotype and consequently atherosclerosis in mice. Moreover, the activity levels of Akt signaling determine the viability of monocytes/macrophages and their resistance to pro-apoptotic stimuli in atherosclerotic lesions. Therefore, elimination of pro-apoptotic factors as well as factors that antagonize or suppress Akt signaling in macrophages increases cell viability, protecting them from apoptosis, and this markedly accelerates atherosclerosis in mice. In contrast, inhibition of Akt signaling by the ablation of Rictor in myeloid cells, which disrupts mTORC2 assembly, significantly decreases the viability and proliferation of blood monocytes and macrophages with the suppression of atherosclerosis. In addition, monocytes and macrophages exhibit a threshold effect for Akt protein levels in their ability to survive. Ablation of two Akt isoforms, preserving only a single Akt isoform in myeloid cells, markedly compromises monocyte and macrophage viability, inducing monocytopenia and diminishing early atherosclerosis. These recent advances in our understanding of Akt signaling in macrophages in atherosclerosis may have significant relevance in the burgeoning field of cardio-oncology, where PI3K/Akt inhibitors being tested in cancer patients can have significant cardiovascular and metabolic ramifications.
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12 MeSH Terms
Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner.
Gowrikumar S, Ahmad R, Uppada SB, Washington MK, Shi C, Singh AB, Dhawan P
(2019) Oncogene 38: 5321-5337
MeSH Terms: Animals, Biomarkers, Tumor, Cells, Cultured, Claudin-1, Colitis, Colonic Neoplasms, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Inflammatory Bowel Diseases, Intestinal Mucosa, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Prognosis, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Receptors, Notch, Signal Transduction, Up-Regulation, beta Catenin
Show Abstract · Added April 24, 2019
In IBD patients, integration between a hyper-activated immune system and epithelial cell plasticity underlies colon cancer development. However, molecular regulation of such a circuity remains undefined. Claudin-1 (Cld-1), a tight-junction integral protein deregulation alters colonic epithelial cell (CEC) differentiation, and promotes colitis severity while impairing colitis-associated injury/repair. Tumorigenesis is a product of an unregulated wound-healing process and therefore we postulated that upregulated Cld-1 levels render IBD patients susceptible to the colitis-associated cancer (CAC). Villin Cld-1 mice are used to carryout overexpressed studies in mice. The role of deregulated Cld-1 expression in CAC and the underlying mechanism was determined using a well-constructed study scheme and mouse models of DSS colitis/recovery and CAC. Using an inclusive investigative scheme, we here report that upregulated Cld-1 expression promotes susceptibility to the CAC and its malignancy. Increased mucosal inflammation and defective epithelial homeostasis accompanied the increased CAC in Villin-Cld-1-Tg mice. We further found significantly increased levels of protumorigenic M2 macrophages and β-cateninSer552 (β-CatSer552) expression in the CAC in Cld-1Tg vs. WT mice. Mechanistic studies identified the role of PI3K/Akt signaling in Cld-1-dependent activation of the β-CatSer552, which, in turn, was dependent on proinflammatory signals. Our studies identify a critical role of Cld-1 in promoting susceptibility to CAC. Importantly, these effects of deregulated Cld-1 were not associated with altered tight junction integrity, but on its noncanonical role in regulating Notch/PI3K/Wnt/ β-CatSer552 signaling. Overall, outcome from our current studies identifies Cld-1 as potential prognostic biomarker for IBD severity and CAC, and a novel therapeutic target.
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22 MeSH Terms
Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and activation loop mutants in GISTs preclinical models.
Lu T, Chen C, Wang A, Jiang Z, Qi Z, Hu Z, Hu C, Liu F, Wang W, Wu H, Wang B, Wang L, Qi S, Wu J, Wang W, Tang J, Yan H, Bai M, Liu Q, Liu J
(2019) Cancer Lett 447: 105-114
MeSH Terms: Anilides, Antineoplastic Agents, Cell Line, Tumor, Drug Repositioning, Drug Resistance, Neoplasm, Gastrointestinal Stromal Tumors, Humans, Imatinib Mesylate, Mutation, Proto-Oncogene Proteins c-kit, Pyridines
Show Abstract · Added April 2, 2019
Despite of the great success of imatinib as the first-line treatment for GISTs, the majority of patients will develop drug-acquired resistance due to secondary mutations in the cKIT kinase. Sunitinib and regorafenib have been approved as the second and third line therapies to overcome some of these drug-resistance mutations; however, their limited clinical response, toxicity and resistance of the activation loop mutants still makes new therapies bearing different cKIT mutants activity spectrum profile highly demanded. Through a drug repositioning approach, we found that cabozantinib exhibited higher potency than imatinib against primary gain-of-function mutations of cKIT. Moreover, cabozantinib was able to overcome cKIT gatekeeper T670I mutation and the activation loop mutations that are resistant to imatinib or sunitinib. Cabozantinib demonstrated good efficacy in vitro and in vivo in the cKIT mutant-driven preclinical models of GISTs while displaying a long-lasting effect after treatment withdrawal. Furthermore, it also exhibited dose-dependent anti-proliferative efficacy in the GIST patient derived primary cells. Considering clinical safety and PK profile of cabozantinib, this report provides the basis for the future clinical applications of cabozantinib as an alternative anti-GISTs therapy in precision medicine.
Copyright © 2019 Elsevier B.V. All rights reserved.
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11 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
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9 MeSH Terms