The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
Dean W Felsher - One of the best experts on this subject based on the ideXlab platform.
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myc master regulator of immune privilege
Trends in Immunology, 2017Co-Authors: Stephanie C Casey, Virginie Baylot, Dean W FelsherAbstract:Cancers are often initiated by genetic events that activate proto-Oncogenes or inactivate tumor-suppressor genes. These events are also crucial for sustained tumor cell proliferation and survival, a phenomenon described as Oncogene addiction. In addition to this cell-intrinsic role, recent evidence indicates that Oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many Oncogenes or loss of tumor suppressors induces the expression of immune checkpoints that regulate the immune response, such as PD-L1. We discuss here how Oncogenes, and in particular MYC, suppress immune surveillance, and how Oncogene-targeted therapies may restore the immune response against tumors.
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bim mediated apoptosis and Oncogene addiction
Aging (Albany NY), 2016Co-Authors: Yulin Li, Anja Deutzmann, Dean W FelsherAbstract:Oncogene addiction is a phenomenon whereby suppression of a driver Oncogene is associated with dramatic tumor regression that has been observed in experimental models and in response to targeted therapies [1]. However, the mechanism by which Oncogene inactivation induces this massive reduction in tumor burden is not clear. In tumors addicted to the MYC Oncogene, suppression of this Oncogene leads to tumor regression that is associated with a marked increase in apoptosis. This at first glance appears to be paradoxical since generally Oncogene activation, and MYC activation in particular, is associated with increased apoptosis. Recently, we have described a possible mechanism that may explain why inactivation of pro-apoptotic Oncogenes, such as MYC, induce apoptosis [2].
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Abstract IA12: Mechanisms of MYC addiction
Molecular Cancer Research, 2015Co-Authors: Dean W FelsherAbstract:Many human cancers are caused by the activation of the MYC Oncogene. We have developed experimental transgenic mouse models to model and predict the therapeutic efficacy of targeted therapy of Oncogenes. Using the Tet system, we can conditionally regulate Oncogene expression in vivo in a temporally controlled and tissue specific manner. We have shown that many Oncogenes (MYC, RAS, BCR-ABL) induce tumorigenesis that is completely reversible upon their inactivation. We have described this phenomenon as Oncogene addiction. Oncogene addiction is associated with proliferative arrest, apoptosis, differentiation, cellular senescence and the shutdown of angiogenesis. The specific consequences of MYC Oncogene inactivation depend both on the genetic and cellular context. In some cases, even brief inactivation of an Oncogene can result in sustained tumor regression. In other cases, Oncogene inactivation is associated with tumor dormancy. Tumor cell intrinsic and host-dependent cell autonomous mechanisms are involved. Tumor cell intrinsic mechanisms appear to involve mechanisms that are dependent upon DNA repair processes, the regulation of protein synthesis and of cellular metabolism. Host-dependent mechanisms include the regulation of angiogenesis and immune cell elimination. In addition, tumor cells secrete autocrine factors critical to Oncogene addiction. We have uncovered that Oncogene addiction is both dependent upon cell autonomous and host cell dependent mechanisms. Thus, MYC via miR17-92 regulates chromatin regulatory gene products required to in a cell autonomous manner regulate cellular proliferation, survival and self-renewal programs. However, MYC through regulation of host immune mechanisms and the recruitement of CD4+ T-cells, in a host cell dependent manner, regulates the tumor microenvironment. Our experimental model systems have been employed to generate nanotechnologies and molecular imaging approaches as well as innovative therapies to respectively predict and to elicit MYC addiction. Citation Format: Dean Felsher. Mechanisms of MYC addiction. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA12.
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myc inactivation elicits Oncogene addiction through both tumor cell intrinsic and host dependent mechanisms
Genes & Cancer, 2010Co-Authors: Dean W FelsherAbstract:Tumorigenesis is generally caused by genetic changes that activate Oncogenes or inactivate tumor suppressor genes. The targeted inactivation of Oncogenes can be associated with tumor regression through the phenomenon of Oncogene addiction. One of the most common oncogenic events in human cancer is the activation of the MYC Oncogene. The inactivation of MYC may be a general and effective therapy for human cancer. Indeed, it has been experimentally shown that the inactivation of MYC can result in dramatic and sustained tumor regression in lymphoma, leukemia, osteosarcoma, hepatocellular carcinoma, squamous carcinoma, and pancreatic carcinoma through a multitude of mechanisms, including proliferative arrest, terminal differentiation, cellular senescence, induction of apoptosis, and the shutdown of angiogenesis. Cell-autonomous and cell-dependent mechanisms have both been implicated, and recent results suggest a critical role for autocrine factors, including thrombospondin-1 and TGF-β. Hence, targeting the inactivation of MYC appears to elicit Oncogene addiction and, thereby, tumor regression through both tumor cell–intrinsic and host-dependent mechanisms.
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MYC Inactivation Elicits Oncogene Addiction through Both Tumor Cell–Intrinsic and Host-Dependent Mechanisms
Genes & Cancer, 2010Co-Authors: Dean W FelsherAbstract:Tumorigenesis is generally caused by genetic changes that activate Oncogenes or inactivate tumor suppressor genes. The targeted inactivation of Oncogenes can be associated with tumor regression through the phenomenon of Oncogene addiction. One of the most common oncogenic events in human cancer is the activation of the MYC Oncogene. The inactivation of MYC may be a general and effective therapy for human cancer. Indeed, it has been experimentally shown that the inactivation of MYC can result in dramatic and sustained tumor regression in lymphoma, leukemia, osteosarcoma, hepatocellular carcinoma, squamous carcinoma, and pancreatic carcinoma through a multitude of mechanisms, including proliferative arrest, terminal differentiation, cellular senescence, induction of apoptosis, and the shutdown of angiogenesis. Cell-autonomous and cell-dependent mechanisms have both been implicated, and recent results suggest a critical role for autocrine factors, including thrombospondin-1 and TGF-β. Hence, targeting the inactivation of MYC appears to elicit Oncogene addiction and, thereby, tumor regression through both tumor cell–intrinsic and host-dependent mechanisms.
Thanos D Halazonetis - One of the best experts on this subject based on the ideXlab platform.
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intragenic origins due to short g1 phases underlie Oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene activation results in firing of ectopic origins of replication within transcribed genes, resulting in replication stress and genome instability. Oncogenes can cause genome instability by inducing replication stress, but the molecular mechanisms that underpin this process were unknown. Morgane Macheret and Thanos Halazonetis demonstrate that Oncogene activation in human cancer cells results in firing of ectopic origins of replication within transcribed genes. These origins are normally quiescent, as they are suppressed by transcription. When activated, these intragenic origins lead to conflicts between replication and transcription, resulting in collapsed replication forks, double-stranded breaks and translocations. Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer1,2,3,4. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from Oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of Oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
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intragenic origins due to short g1 phases underlie Oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from Oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of Oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
Morgane Macheret - One of the best experts on this subject based on the ideXlab platform.
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intragenic origins due to short g1 phases underlie Oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene activation results in firing of ectopic origins of replication within transcribed genes, resulting in replication stress and genome instability. Oncogenes can cause genome instability by inducing replication stress, but the molecular mechanisms that underpin this process were unknown. Morgane Macheret and Thanos Halazonetis demonstrate that Oncogene activation in human cancer cells results in firing of ectopic origins of replication within transcribed genes. These origins are normally quiescent, as they are suppressed by transcription. When activated, these intragenic origins lead to conflicts between replication and transcription, resulting in collapsed replication forks, double-stranded breaks and translocations. Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer1,2,3,4. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from Oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of Oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
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intragenic origins due to short g1 phases underlie Oncogene induced dna replication stress
Nature, 2018Co-Authors: Morgane Macheret, Thanos D HalazonetisAbstract:Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. However, elucidating how Oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the Oncogenes CCNE1 and MYC. Remarkably, both Oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated Oncogenes. Forks from Oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of Oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.
Donald S. Torry - One of the best experts on this subject based on the ideXlab platform.
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Proto‐Oncogenes and Germ‐Cell Differentiation
American Journal of Reproductive Immunology, 1992Co-Authors: Donald S. TorryAbstract:: Oncogenes are identified functionally by their ability to induce neoplastic transformation of susceptible cells. The first Oncogenes to be characterized were isolated from acutely transforming retroviruses. Subsequently, it was determined that the retroviral Oncogenes were formed from normal, progenitor genes. These cellular homologs of the viral Oncogenes are termed proto-Oncogenes. The derivation of Oncogenes from proto-Oncogenes is the consequence of mutations that remove regulatory constraints from the proto-Oncogene. The ability of Oncogenes to induce transformation implies that proto-Oncogenes may function in growth and differentiation pathways in normal cells. Although many proto-Oncogenes have been defined, the normal physiological function of most is not known. Studies of proto-Oncogene expression during normal game-togenesis have determined that some genes are expressed in a stage-specific manner. The use of germ cells to provide homogeneous and defined normal cell populations facilitates identifying the roles proto-Oncogenes have in regulating cell growth and differentiation.
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Proto-Oncogenes and germ-cell differentiation.
American journal of reproductive immunology (New York N.Y. : 1989), 1992Co-Authors: Donald S. TorryAbstract:: Oncogenes are identified functionally by their ability to induce neoplastic transformation of susceptible cells. The first Oncogenes to be characterized were isolated from acutely transforming retroviruses. Subsequently, it was determined that the retroviral Oncogenes were formed from normal, progenitor genes. These cellular homologs of the viral Oncogenes are termed proto-Oncogenes. The derivation of Oncogenes from proto-Oncogenes is the consequence of mutations that remove regulatory constraints from the proto-Oncogene. The ability of Oncogenes to induce transformation implies that proto-Oncogenes may function in growth and differentiation pathways in normal cells. Although many proto-Oncogenes have been defined, the normal physiological function of most is not known. Studies of proto-Oncogene expression during normal game-togenesis have determined that some genes are expressed in a stage-specific manner. The use of germ cells to provide homogeneous and defined normal cell populations facilitates identifying the roles proto-Oncogenes have in regulating cell growth and differentiation.
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Proto-Oncogenes in development and cancer.
American Journal of Reproductive Immunology, 1991Co-Authors: Donald S. Torry, Geoffrey M CooperAbstract:: Although analogies are often made comparing development to cancer, there is of course a major difference. Normal development requires complex patterns of rigidly controlled cell proliferation and differentiation. In contrast, cancer represents the pathological condition that results when normal cell growth patterns are uncoupled from their regulatory influences. Genetic studies of RNA tumor viruses have provided insights into the relationships and differences of the genes responsible for normal development and cancer. The presence of discrete genes (Oncogenes) within the genome of oncogenic retroviruses is responsible for their tumor-igenic potential. Molecular genetic studies have found that normal eukaryotic cells possess genes that are quite homologous to the retroviral Oncogenes. These normal cellular genes (proto-Oncogenes) are involved in the regulation of proliferation and differentiation. However, if mutated, proto-Oncogenes have the potential for inducing neoplastic transformation. The conversion of a proto-Oncogene to an Oncogene is called activation. Proto-Oncogenes can become activated by a variety of genetic mechanisms including transduction, insertional mutagenesis, amplification, point mutations, and chromosomal translocations. In each instance the genetic aberration results in a proto-Oncogene that is now free of its normal regulatory constraints. Such deregulation of function imparts a distinct growth advantage to the cell.
Harold E Varmus - One of the best experts on this subject based on the ideXlab platform.
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Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by myc and mutant kras
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Katrina Podsypanina, Katerina Politi, Levi J Beverly, Harold E VarmusAbstract:Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating Oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two Oncogenes remain dependent on the activity of a single Oncogene. Deinduction of either Oncogene individually, or both Oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of KrasG12D in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and KrasG12D transgenes further improved survival. Disease relapse after deinduction of both Oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTV-rtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of Oncogenes and that targeted approaches will also benefit from combination therapies.
