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Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion.
Marazioti A, Lilis I, Vreka M, Apostolopoulou H, Kalogeropoulou A, Giopanou I, Giotopoulou GA, Krontira AC, Iliopoulou M, Kanellakis NI, Agalioti T, Giannou AD, Jones-Paris C, Iwakura Y, Kardamakis D, Blackwell TS, Taraviras S, Spella M, Stathopoulos GT
(2018) Nat Commun 9: 672
MeSH Terms: Animals, Cell Line, Tumor, Chemokine CXCL1, Female, Genes, ras, Humans, I-kappa B Kinase, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Mutation, Myeloid Cells, NF-kappa B, Pleural Effusion, Malignant, Receptors, Interleukin-1
Show Abstract · Added March 21, 2018
Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKKα-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1β. Indeed, IKKα is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-κB signaling. IL-1β fuels addiction of mutant KRAS to IKKα resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1β-mediated NF-κB induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKKα, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKKα-mediated responsiveness of tumor cells to host IL-1β, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.
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16 MeSH Terms
Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy.
Kasper S, Reis H, Ziegler S, Nothdurft S, Mueller A, Goetz M, Wiesweg M, Phasue J, Ting S, Wieczorek S, Even A, Worm K, Pogorzelski M, Breitenbuecher S, Meiler J, Paul A, Trarbach T, Schmid KW, Breitenbuecher F, Schuler M
(2017) Oncotarget 8: 45898-45917
MeSH Terms: Antineoplastic Agents, Immunological, Apoptosis, Biomarkers, Cell Line, Tumor, Colorectal Neoplasms, Drug Resistance, Neoplasm, ErbB Receptors, Exons, Genes, ras, Humans, Mitogen-Activated Protein Kinases, Mutation, Odds Ratio, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Signal Transduction
Show Abstract · Added March 17, 2018
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC. Oncogenic RAS activates the MAPK and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways in RAS-mutant CRC is less defined. A better mechanistic understanding of RAS-mediated resistance may guide development of rational intervention strategies. To this end we developed cancer models for functional dissection of resistance to anti-EGFR therapy in vitro and in vivo. To selectively activate MAPK- or AKT-signaling we expressed conditionally activatable RAF-1 and AKT in cancer cells. We found that either pathway independently protected sensitive cancer models against anti-EGFR antibody treatment in vitro and in vivo. RAF-1- and AKT-mediated resistance was associated with increased expression of anti-apoptotic BCL-2 proteins. Biomarkers of MAPK and PI3K/AKT pathway activation correlated with inferior outcome in a cohort of mCRC patients receiving cetuximab-based therapy. Dual pharmacologic inhibition of PI3K and MEK successfully sensitized primary resistant CRC models to anti-EGFR therapy. In conclusion, combined targeting of MAPK and PI3K/AKT signaling, but not single pathways, may be required to enhance the efficacy of anti-EGFR antibody therapy in patients with RAS-mutated CRC as well as in RAS wild type tumors with clinical resistance.
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17 MeSH Terms
Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.
McFadden DG, Politi K, Bhutkar A, Chen FK, Song X, Pirun M, Santiago PM, Kim-Kiselak C, Platt JT, Lee E, Hodges E, Rosebrock AP, Bronson RT, Socci ND, Hannon GJ, Jacks T, Varmus H
(2016) Proc Natl Acad Sci U S A 113: E6409-E6417
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Animals, Carcinogens, Cell Transformation, Neoplastic, DNA Copy Number Variations, DNA Mutational Analysis, Disease Models, Animal, ErbB Receptors, Gene Dosage, Genes, myc, Genes, ras, Genome-Wide Association Study, Lung Neoplasms, Mice, Mice, Transgenic, Mutation, Point Mutation, ROC Curve, Whole Exome Sequencing
Show Abstract · Added April 26, 2017
Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.
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20 MeSH Terms
Expression of Activated Ras in Gastric Chief Cells of Mice Leads to the Full Spectrum of Metaplastic Lineage Transitions.
Choi E, Hendley AM, Bailey JM, Leach SD, Goldenring JR
(2016) Gastroenterology 150: 918-30.e13
MeSH Terms: Animals, Anticarcinogenic Agents, Benzimidazoles, Cell Differentiation, Cell Lineage, Cell Proliferation, Cell Transformation, Neoplastic, Chief Cells, Gastric, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Genes, ras, Genetic Predisposition to Disease, Humans, Macrophages, Male, Metaplasia, Mice, Inbred C57BL, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases, Mutation, Phenotype, Protein Kinase Inhibitors, Signal Transduction, Stomach Neoplasms, Time Factors, Transcriptional Activation
Show Abstract · Added March 28, 2016
BACKGROUND & AIMS - Gastric cancer develops in the context of parietal cell loss, spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM). We investigated whether expression of the activated form of Ras in gastric chief cells of mice leads to the development of SPEM, as well as progression of metaplasia.
METHODS - We studied Mist1-CreERT2Tg/+;LSL-K-Ras(G12D)Tg/+ (Mist1-Kras) mice, which express the active form of Kras in chief cells on tamoxifen exposure. We studied Mist1-CreERT2Tg/+;LSL-KRas (G12D)Tg/+;R26RmTmG/+ (Mist1-Kras-mTmG) mice to examine whether chief cells that express active Kras give rise to SPEM and IM. Some mice received intraperitoneal injections of the Mitogen-activated protein kinase kinase (MEK) inhibitor, selumetinib, for 14 consecutive days. Gastric tissues were collected and analyzed by immunohistochemistry, immunofluorescence, and quantitative polymerase chain reaction.
RESULTS - Mist1-Kras mice developed metaplastic glands, which completely replaced normal fundic lineages and progressed to IM within 3-4 months after tamoxifen injection. The metaplastic glands expressed markers of SPEM and IM, and were infiltrated by macrophages. Lineage tracing studies confirmed that the metaplasia developed directly from Kras (G12D)-induced chief cells. Selumetinib induced persistent regression of SPEM and IM, and re-established normal mucosal cells, which were derived from normal gastric progenitor cells.
CONCLUSIONS - Expression of activated Ras in chief cells of Mist1-Kras mice led to the full range of metaplastic lineage transitions, including SPEM and IM. Inhibition of Ras signaling by inhibition of MEK might reverse preneoplastic metaplasia in the stomach.
Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
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27 MeSH Terms
KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine.
Stewart ML, Tamayo P, Wilson AJ, Wang S, Chang YM, Kim JW, Khabele D, Shamji AF, Schreiber SL
(2015) Cancer Res 75: 2897-906
MeSH Terms: Animals, Azacitidine, Biomarkers, Tumor, Cystadenocarcinoma, Serous, Decitabine, Drug Resistance, Neoplasm, Female, Genes, ras, Humans, Mice, Mice, Nude, Mice, Transgenic, Mutation, Ovarian Neoplasms, Prognosis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Show Abstract · Added February 22, 2016
Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells. Pretreatment with decitabine decreased the cytotoxic activity of MEK inhibitors in KRAS-mutant ovarian cancer cells, with reciprocal downregulation of DNMT1 and MEK/ERK phosphorylation. In parallel with these responses, decitabine also upregulated the proapoptotic BCL-2 family member BNIP3, which is known to be regulated by MEK and ERK, and heightened the activity of proapoptotic small-molecule navitoclax, a BCL-2 family inhibitor. In a xenograft model of KRAS-mutant ovarian cancer, combining decitabine and navitoclax heightened antitumor activity beyond administration of either compound alone. Our results define the RAS/MEK/DNMT1 pathway as a determinant of sensitivity to DNA methyltransferase inhibition, specifically implicating KRAS status as a biomarker of drug response in ovarian cancer.
©2015 American Association for Cancer Research.
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17 MeSH Terms
Ovarian mucinous tumor with malignant mural nodules: dedifferentiation or collision?
Desouki MM, Khabele D, Crispens MA, Fadare O
(2015) Int J Gynecol Pathol 34: 19-24
MeSH Terms: Carcinoma, Cell Movement, Cell Transformation, Neoplastic, Combined Modality Therapy, Drug Therapy, Female, Genes, ras, Humans, Mutation, Neoplasms, Cystic, Mucinous, and Serous, Ovarian Neoplasms, Ovariectomy, Proto-Oncogene Proteins B-raf, Treatment Outcome, Young Adult
Show Abstract · Added February 19, 2015
Ovarian mucinous tumors with mural nodules are rare surface epithelial-stromal tumors. The mural nodules are divergent neoplasms that may be benign or malignant. The latter may be in the form of a sarcoma, carcinosarcoma, anaplastic carcinoma, or a variety of other recognized histotypes of carcinoma, which raises the question of whether malignant mural nodules represent a form of dedifferentiation in ovarian mucinous tumors or whether they represent collision tumors. We recently reported the K-RAS gene mutation status in a case of ovarian mucinous adenocarcinoma with mural nodule of high-grade sarcoma. The mucinous and sarcomatous components revealed a mutation in codon 12 of the K-RAS gene of a different nucleotide substitution, indicating that these 2 tumor components were different clones of the same tumor. Herein, we are reporting another case of a 20-yr-old woman who presented with 22 cm pelvic mass, omental caking, and ascites. A diagnosis of invasive mucinous carcinoma with mural nodules of anaplastic carcinoma was rendered. K-RAS gene mutation studies revealed p.G12V, c.35G>T mutation in the 2 components of the tumor, which is the most common mutation reported in mucinous tumors of the ovary. The fact that sarcomatous or anaplastic carcinomatous mural nodules in ovarian mucinous tumors display the same K-RAS mutations as their underlying mucinous neoplasms provides supportive evidence that at least some malignant mural nodules represent a form of dedifferentiation in ovarian mucinous tumors, rather than a collision of 2 divergent tumor types.
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15 MeSH Terms
Beyond exon 2--the developing story of RAS mutations in colorectal cancer.
Berlin J
(2013) N Engl J Med 369: 1059-60
MeSH Terms: Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Colorectal Neoplasms, ErbB Receptors, Fluorouracil, Genes, ras, Humans, Leucovorin, Organoplatinum Compounds, Panitumumab, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), ras Proteins
Added March 20, 2014
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14 MeSH Terms
Distinct molecular features of colorectal cancer in Ghana.
Raskin L, Dakubo JC, Palaski N, Greenson JK, Gruber SB
(2013) Cancer Epidemiol 37: 556-61
MeSH Terms: African Americans, Colorectal Neoplasms, DNA Mismatch Repair, DNA, Neoplasm, Exons, Female, Genes, ras, Ghana, Humans, Immunohistochemistry, Male, Microsatellite Instability, Middle Aged, Molecular Epidemiology, Paraffin Embedding, Proto-Oncogene Proteins B-raf
Show Abstract · Added March 7, 2014
OBJECTIVES - While colorectal cancer (CRC) is common, its incidence significantly varies around the globe. The incidence of CRC in West Africa is relatively low, but it has a distinctive clinical pattern and its molecular characteristics have not been studied. This study is one of the first attempts to analyze molecular, genetic, and pathological characteristics of colorectal cancer in Ghana.
METHODS - DNA was extracted from microdissected tumor and adjacent normal tissue of 90 paraffin blocks of CRC cases (1997-2007) collected at the University of Ghana. Microsatellite instability (MSI) was determined using fragment analysis of ten microsatellite markers. We analyzed expression of mismatch repair (MMR) proteins by immunohistochemistry and sequenced exons 2 and 3 of KRAS and exon 15 of BRAF.
RESULTS - MSI analysis showed 41% (29/70) MSI-High, 20% (14/70) MSI-Low, and 39% (27/70) microsatellite-stable (MSS) tumors. Sequencing of KRAS exons 2 and 3 identified activating mutations in 32% (24/75) of tumors, and sequencing of BRAF exon 15, the location of the common activating mutation (V600), did not show mutations at codons 599 and 600 in 88 tumors.
CONCLUSIONS - Our study found a high frequency of MSI-High colorectal tumors (41%) in Ghana. While the frequency of KRAS mutations is comparable with other populations, absence of BRAF mutations is intriguing and would require further analysis of the molecular epidemiology of CRC in West Africa.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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16 MeSH Terms
Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma.
Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JP, Pan FC, Akiyama H, Wright CV, Jensen K, Hebrok M, Sander M
(2012) Cancer Cell 22: 737-50
MeSH Terms: Acinar Cells, Carcinoma, Pancreatic Ductal, Genes, ras, Humans, Metaplasia, Mutation, Pancreatic Neoplasms, Precancerous Conditions, SOX9 Transcription Factor
Show Abstract · Added March 20, 2014
Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.
Copyright © 2012 Elsevier Inc. All rights reserved.
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9 MeSH Terms
EGF receptor is required for KRAS-induced pancreatic tumorigenesis.
Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT
(2012) Cancer Cell 22: 304-17
MeSH Terms: ADAM Proteins, ADAM17 Protein, Animals, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Transformation, Neoplastic, Epithelial Cells, ErbB Receptors, Extracellular Signal-Regulated MAP Kinases, Genes, ras, Humans, Mice, Mice, Transgenic, Pancreas, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras)
Show Abstract · Added April 12, 2016
Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
Copyright © 2012 Elsevier Inc. All rights reserved.
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16 MeSH Terms