The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Christopher M Counter - One of the best experts on this subject based on the ideXlab platform.
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Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer.
PLOS ONE, 2015Co-Authors: Jamie D Weyandt, Benjamin L. Lampson, Sherry Tang, Matthew Mastrodomenico, Diana M. Cardona, Christopher M CounterAbstract:Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and Hras, which can be activated in the presence of oncogenic KRAS. The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enhance or inhibit tumorigenesis depending upon the context. As pancreatic cancer is critically dependent upon Ras signaling, we tested and now report that loss of Hras increases tumor load and reduces survival in an oncogenic KRAS-driven pancreatic adenocarcinoma mouse model. These effects were traced to the earliest stages of pancreatic cancer, suggesting that wild-type Hras may suppress tumor initiation. In normal cells, activated Ras can suppress proliferation through p53-dependent mechanisms. We find that the tumor suppressive effects of Hras are nullified in a homozygous mutant p53 background. As such, loss of wild-type Hras fosters the earliest stages of pancreatic cancer in a p53-dependent manner.
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abstract 4426 tumor suppressive effects of wild type hras on oncogenic KRAS driven pancreatic tumorigenesis
Cancer Research, 2014Co-Authors: Jamie D Weyandt, Christopher M CounterAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The RAS proteins are a group of small GTPases that can become constitutively activated by point mutations that are found in a quarter or more of all cancer patients, particularly in pancreatic cancer, in which over 90% of patients have an activating KRAS mutation. There are three well-characterized RAS protein family members: HRAS, NRAS, and KRAS, the latter of which is alternatively spliced at the C-terminus into two proteins, KRAS4A and KRAS4B. The RAS proteins are all nearly identical at their N-termini and core effector binding domains. However, they have divergent C-terminal membrane-binding regions that impart both different subcellular localization and subtle changes in signaling. While oncogenic RAS is well established to promote cancer, recent work has suggested that wild-type RAS proteins also participate in tumorigenesis. In this regard, we previously found that wild-type HRAS is activated downstream of oncogenic KRAS, which promoted tumor growth of human pancreatic cancer cell lines. To examine the role of wild-type Hras during de novo pancreatic tumor development, we tested whether knockout of the wild-type Hras gene altered tumorigenesis in oncogenic KRAS-driven mice models of pancreatic cancer. Specifically, Hras homozygous null mice (Hras-/-) were crossed into a Pdx-Cre;LSL-KRASG12D/+ background in the absence or presence of an additional mutant p53 allele (Trp53R172H/+) to induce early and late pancreatic cancer, respectively. Surprisingly, loss of Hras led to an increase in early pancreatic lesions and reduced survival in the model of late disease. Since HRAS is activated downstream of oncogenic KRAS, and high oncogenic signaling can induce a senescent growth arrest, we tested and found that suppressing senescence by mutating both alleles of Trp53 ameliorated the survival difference between wild-type and null Hras mice. We thus hypothesize that wild-type Hras amplifies oncogenic KRAS signaling, leading to the growth arrest of senescence and thereby inhibit early tumorigenesis. However, once senescence is suppressed later in tumorigenesis, wild-type RAS proteins instead promote more malignant phenotypes. Citation Format: Jamie D. Weyandt, Christopher M. Counter. Tumor suppressive effects of wild-type Hras on oncogenic KRAS-driven pancreatic tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4426. doi:10.1158/1538-7445.AM2014-4426
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rare codons regulate KRAS oncogenesis
Current Biology, 2013Co-Authors: Benjamin L. Lampson, Nicole L K Pershing, Joseph A Prinz, Joshua R Lacsina, William F Marzluff, Christopher V Nicchitta, David M Macalpine, Christopher M CounterAbstract:Summary Oncogenic mutations in the small Ras GTPases KRAS, HRas, and NRas render the proteins constitutively GTP bound and active, a state that promotes cancer [1]. Ras proteins share ∼85% amino acid identity [2], are activated by [3] and signal through [4] the same proteins, and can exhibit functional redundancy [5, 6]. Nevertheless, manipulating expression or activation of each isoform yields different cellular responses [7–10] and tumorigenic phenotypes [11–13], even when different ras genes are expressed from the same locus [6]. We now report a novel regulatory mechanism hardwired into the very sequence of RAS genes that underlies how such similar proteins impact tumorigenesis differently. Specifically, despite their high sequence similarity, KRAS is poorly translated compared to HRAS due to enrichment in genomically underrepresented or rare codons. Converting rare to common codons increases KRAS expression and tumorigenicity to mirror that of HRas. Furthermore, in a genome-wide survey, similar gene pairs with opposing codon bias were identified that not only manifest dichotomous protein expression but also are enriched in key signaling protein classes and pathways. Thus, synonymous nucleotide differences affecting codon usage account for differences between HRas and KRAS expression and function and may represent a broader regulation strategy in cell signaling.
Allan Balmain - One of the best experts on this subject based on the ideXlab platform.
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interactions between wild type and mutant ras genes in lung and skin carcinogenesis
Oncogene, 2013Co-Authors: Minh D To, Peter M K Westcott, Karl Luke Banta, Reyno Del Rosario, Allan BalmainAbstract:Ras oncogenes (Hras, KRAS and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT KRAS is observed only in mutant KRAS-driven lung carcinogenesis, where loss of one KRAS allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the KRAS proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant KRAS in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant KRAS-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.
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inflammation and hras signaling control epithelial mesenchymal transition during skin tumor progression
Genes & Development, 2013Co-Authors: Christine Wong, David A Quigley, Kuangyu Jen, Phillips Y Huang, Reyno Del Rosario, Allan BalmainAbstract:Epithelial–mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%–30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic inflammation causes a dramatic reduction in classical papillomas and squamous cell carcinomas (SCCs), but the mice still develop highly invasive carcinomas with EMT properties, reduced levels of Hras and Egfr signaling, and frequent Ink4/Arf deletions. Deletion of Hras from the mouse germline also leads to a strong reduction in squamous tumor development, but tumors now acquire activating KRAS mutations and exhibit more aggressive metastatic properties. We propose that invasive carcinomas can arise by different genetic and biological routes dependent on exposure to chronic inflammation and possibly from different target cell populations within the skin. Our data have implications for the use of inhibitors of inflammation or of Ras/Egfr pathway signaling for prevention or treatment of invasive cancers.
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KRAS regulatory elements and exon 4a determine mutation specificity in lung cancer
Nature Genetics, 2008Co-Authors: Minh D To, Reyno Del Rosario, Anthony N. Karnezis, Christine Wong, Roberto Di Lauro, Allan BalmainAbstract:Ras family genes are common targets for somatic mutations in human cancer: KRAS is frequently mutated in lung carcinomas, whereas HRAS mutations are common in skin tumors. Allan Balmain and colleagues use genetic engineering of ras genes in mice to show that specificity for ras mutations is determined by local regulatory elements, and that KRAS 4A is the major oncogenic isoform of KRAS. KRAS is the most frequently mutated ras family member in lung carcinomas1,2, whereas Hras mutations are common in tumors from stratified epithelia such as the skin. Using a Hras knock-in mouse model3, we demonstrate that specificity for KRAS mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target ras genes. Although the KRAS 4A isoform is dispensable for mouse development4,5, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wild-type (WT) KRAS on the mutant allele6,7. KRAS 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The two KRAS isoforms undergo different post-translational modifications8; therefore, these findings can have implications for the design of therapeutic strategies for inhibiting oncogenic KRAS activity in human cancers.
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KRAS mutation selectivity and isoform specificity in lung cancer
Molecular Cancer Therapeutics, 2007Co-Authors: Minh D To, Reyno Del Rosario, Anthony N. Karnezis, Christine Wong, Roberto Di Lauro, Allan BalmainAbstract:C17 Activating KRAS mutations occur in 15-30% of human lung adenocarcinomas, and in the majority of carcinogen induced lung tumors in the mouse, highlighting the importance of KRAS in lung carcinogenesis. KRAS deficiency is embryonically lethal, but mice (HrasKI) with the Hras coding sequence placed into the KRAS locus on chromosome 6 are viable. We show that urethane treated HrasKI mice develop ~10-fold more lung tumors than wild-type (WT) mice in spite of lacking KRAS expression. The KRAS protein is therefore not essential for lung carcinogenesis. However, while most lung tumors in this model exhibit activating mutations at codon 61 in the inserted HrasKI allele, no mutations are found at the corresponding position in the endogenous Hras locus on chromosome 7. These results demonstrate that the mechanism of KRAS mutation selectivity during lung carcinogenesis involves specific regulatory elements within or near the KRAS gene. Two alternative splicing isoforms of KRAS, designated 4A and 4B, are present in the lung. KRAS-4B is the major isoform and is thought to be the major mediator of KRAS function. However, KRASKI mice with the KRAS-4B coding sequence placed back into the endogenous KRAS locus are highly resistant to lung tumor development. Moreover, mutations always occur in the native KRAS gene and not in the KRASKI allele in lung tumors from KRASKI heterozygous animals. These results are consistent with KRAS-4B having a minimal role in lung carcinogenesis and suggest that the major effect of KRAS in lung tumor development is mediated through KRAS-4A. Since KRAS-4A and KRAS-4B proteins undergo distinctive post-translational modifications, these findings can have important implications in the design of therapeutic strategies for inhibiting oncogenic KRAS activity for the treatment of cancer.
Carlo Dominici - One of the best experts on this subject based on the ideXlab platform.
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ras signaling dysregulation in human embryonal rhabdomyosarcoma
Genes Chromosomes and Cancer, 2009Co-Authors: Simone Martinelli, Heather P Mcdowell, Silvia Delle Vigne, George Kokai, Stefania Uccini, Marco Tartaglia, Carlo DominiciAbstract:Rhabdomyosarcoma (RMS) is a common childhood solid tumor, resulting from dysregulation of the skeletal myogenesis program. Two major histological subtypes occur in childhood RMS, embryonal and alveolar. While chromosomal rearrangements account for the majority of alveolar tumors, the genetic defects underlying the pathogenesis of embryonal RMS remain largely undetermined. A few studies performed on small series of embryonal tumors suggest that dysregulation of RAS function may be relevant to disease pathogenesis. To explore further the biological and clinical relevance of mutations with perturbing consequences on RAS signaling in embryonal RMS, we investigated the prevalence of PTPN11, HRAS, KRAS, NRAS, BRAF, MEK1, and MEK2 mutations in a relatively large cohort of primary tumors. While HRAS and KRAS were found to be rarely mutated, we identified somatic NRAS lesions in 20% of cases. All mutations were missense and affected codon 61, with the introduction of a positive charged amino acid residue representing the most common event. PTPN11 was found mutated in one tumor specimen, confirming that somatic defects in this gene are relatively uncommon in RMS, while no mutation was observed in BRAF and MEK genes. Although no clear association of mutations with any clinical variable was observed, comparison of the outcome between mutation-positive and mutation-negative cases indicated a trend for a higher percentage of patients exhibiting a better outcome in the former. Our findings provide evidence that dysregulation of RAS signaling is a major event contributing to embryonal RMS pathogenesis. © 2009 Wiley-Liss, Inc.
Jamie D Weyandt - One of the best experts on this subject based on the ideXlab platform.
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Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer.
PLOS ONE, 2015Co-Authors: Jamie D Weyandt, Benjamin L. Lampson, Sherry Tang, Matthew Mastrodomenico, Diana M. Cardona, Christopher M CounterAbstract:Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and Hras, which can be activated in the presence of oncogenic KRAS. The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enhance or inhibit tumorigenesis depending upon the context. As pancreatic cancer is critically dependent upon Ras signaling, we tested and now report that loss of Hras increases tumor load and reduces survival in an oncogenic KRAS-driven pancreatic adenocarcinoma mouse model. These effects were traced to the earliest stages of pancreatic cancer, suggesting that wild-type Hras may suppress tumor initiation. In normal cells, activated Ras can suppress proliferation through p53-dependent mechanisms. We find that the tumor suppressive effects of Hras are nullified in a homozygous mutant p53 background. As such, loss of wild-type Hras fosters the earliest stages of pancreatic cancer in a p53-dependent manner.
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abstract 4426 tumor suppressive effects of wild type hras on oncogenic KRAS driven pancreatic tumorigenesis
Cancer Research, 2014Co-Authors: Jamie D Weyandt, Christopher M CounterAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The RAS proteins are a group of small GTPases that can become constitutively activated by point mutations that are found in a quarter or more of all cancer patients, particularly in pancreatic cancer, in which over 90% of patients have an activating KRAS mutation. There are three well-characterized RAS protein family members: HRAS, NRAS, and KRAS, the latter of which is alternatively spliced at the C-terminus into two proteins, KRAS4A and KRAS4B. The RAS proteins are all nearly identical at their N-termini and core effector binding domains. However, they have divergent C-terminal membrane-binding regions that impart both different subcellular localization and subtle changes in signaling. While oncogenic RAS is well established to promote cancer, recent work has suggested that wild-type RAS proteins also participate in tumorigenesis. In this regard, we previously found that wild-type HRAS is activated downstream of oncogenic KRAS, which promoted tumor growth of human pancreatic cancer cell lines. To examine the role of wild-type Hras during de novo pancreatic tumor development, we tested whether knockout of the wild-type Hras gene altered tumorigenesis in oncogenic KRAS-driven mice models of pancreatic cancer. Specifically, Hras homozygous null mice (Hras-/-) were crossed into a Pdx-Cre;LSL-KRASG12D/+ background in the absence or presence of an additional mutant p53 allele (Trp53R172H/+) to induce early and late pancreatic cancer, respectively. Surprisingly, loss of Hras led to an increase in early pancreatic lesions and reduced survival in the model of late disease. Since HRAS is activated downstream of oncogenic KRAS, and high oncogenic signaling can induce a senescent growth arrest, we tested and found that suppressing senescence by mutating both alleles of Trp53 ameliorated the survival difference between wild-type and null Hras mice. We thus hypothesize that wild-type Hras amplifies oncogenic KRAS signaling, leading to the growth arrest of senescence and thereby inhibit early tumorigenesis. However, once senescence is suppressed later in tumorigenesis, wild-type RAS proteins instead promote more malignant phenotypes. Citation Format: Jamie D. Weyandt, Christopher M. Counter. Tumor suppressive effects of wild-type Hras on oncogenic KRAS-driven pancreatic tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4426. doi:10.1158/1538-7445.AM2014-4426
Minh D To - One of the best experts on this subject based on the ideXlab platform.
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interactions between wild type and mutant ras genes in lung and skin carcinogenesis
Oncogene, 2013Co-Authors: Minh D To, Peter M K Westcott, Karl Luke Banta, Reyno Del Rosario, Allan BalmainAbstract:Ras oncogenes (Hras, KRAS and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT KRAS is observed only in mutant KRAS-driven lung carcinogenesis, where loss of one KRAS allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the KRAS proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant KRAS in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant KRAS-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.
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KRAS regulatory elements and exon 4a determine mutation specificity in lung cancer
Nature Genetics, 2008Co-Authors: Minh D To, Reyno Del Rosario, Anthony N. Karnezis, Christine Wong, Roberto Di Lauro, Allan BalmainAbstract:Ras family genes are common targets for somatic mutations in human cancer: KRAS is frequently mutated in lung carcinomas, whereas HRAS mutations are common in skin tumors. Allan Balmain and colleagues use genetic engineering of ras genes in mice to show that specificity for ras mutations is determined by local regulatory elements, and that KRAS 4A is the major oncogenic isoform of KRAS. KRAS is the most frequently mutated ras family member in lung carcinomas1,2, whereas Hras mutations are common in tumors from stratified epithelia such as the skin. Using a Hras knock-in mouse model3, we demonstrate that specificity for KRAS mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target ras genes. Although the KRAS 4A isoform is dispensable for mouse development4,5, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wild-type (WT) KRAS on the mutant allele6,7. KRAS 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The two KRAS isoforms undergo different post-translational modifications8; therefore, these findings can have implications for the design of therapeutic strategies for inhibiting oncogenic KRAS activity in human cancers.
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KRAS mutation selectivity and isoform specificity in lung cancer
Molecular Cancer Therapeutics, 2007Co-Authors: Minh D To, Reyno Del Rosario, Anthony N. Karnezis, Christine Wong, Roberto Di Lauro, Allan BalmainAbstract:C17 Activating KRAS mutations occur in 15-30% of human lung adenocarcinomas, and in the majority of carcinogen induced lung tumors in the mouse, highlighting the importance of KRAS in lung carcinogenesis. KRAS deficiency is embryonically lethal, but mice (HrasKI) with the Hras coding sequence placed into the KRAS locus on chromosome 6 are viable. We show that urethane treated HrasKI mice develop ~10-fold more lung tumors than wild-type (WT) mice in spite of lacking KRAS expression. The KRAS protein is therefore not essential for lung carcinogenesis. However, while most lung tumors in this model exhibit activating mutations at codon 61 in the inserted HrasKI allele, no mutations are found at the corresponding position in the endogenous Hras locus on chromosome 7. These results demonstrate that the mechanism of KRAS mutation selectivity during lung carcinogenesis involves specific regulatory elements within or near the KRAS gene. Two alternative splicing isoforms of KRAS, designated 4A and 4B, are present in the lung. KRAS-4B is the major isoform and is thought to be the major mediator of KRAS function. However, KRASKI mice with the KRAS-4B coding sequence placed back into the endogenous KRAS locus are highly resistant to lung tumor development. Moreover, mutations always occur in the native KRAS gene and not in the KRASKI allele in lung tumors from KRASKI heterozygous animals. These results are consistent with KRAS-4B having a minimal role in lung carcinogenesis and suggest that the major effect of KRAS in lung tumor development is mediated through KRAS-4A. Since KRAS-4A and KRAS-4B proteins undergo distinctive post-translational modifications, these findings can have important implications in the design of therapeutic strategies for inhibiting oncogenic KRAS activity for the treatment of cancer.
