Targeting the TGIF/Twist1 network in osteosarcoma
靶向骨肉瘤中的 TGIF/Twist1 网络
基本信息
- 批准号:9311684
- 负责人:
- 金额:$ 34.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-15 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:Adjuvant ChemotherapyAdolescentAttenuatedCDKN2A geneCancer EtiologyCell ProliferationCellsCessation of lifeChildhoodCytostaticsDevelopmentDiagnosisDiseaseEctopic ExpressionEnsureEtiologyExcisionGene ActivationGeneticGenetic TranscriptionGenotypeHomeodomain ProteinsHomeostasisHumanIL10 geneInsertional MutagenesisLaboratoriesLimb BudMalignant Bone NeoplasmMalignant NeoplasmsMediatingMesenchymalMetastatic OsteosarcomaModelingModernizationMolecularMutagenesisNeoplasm MetastasisOperative Surgical ProceduresOsteoblastsOsteogenesisOutcomeOutcome StudyPathogenesisPathologicPatientsPharmacologyPhysiological ProcessesPrognostic MarkerRecurrenceRelapseRoleSamplingSignal PathwaySleeping BeautySuppressor GenesSurvival RateSystemTP53 geneTWIST1 geneTestingTherapeuticTimeTissue MicroarrayTranscription Repressor/CorepressorTreatment EfficacyTumor Suppressor GenesTumor Suppressor ProteinsYeastsage groupbonechemotherapyclinically relevantcohortdesigndrug discoveryexperimental studygenetic signaturegenome sequencinghuman tissueimprovedin vivoinnovationnovel strategiesosteosarcomaoutcome forecastoverexpressionprognosticprogramsprospectivescreeningtumorvirtualwhole genomeyeast two hybrid system
项目摘要
SUMMARY
Osteosarcoma is the most frequent primary malignancy of bone and the second leading cause of cancer-related
death in adolescents. In patients without demonstrable metastasis at the time of diagnosis, surgical resection and
adjuvant chemotherapy have resulted in long-term survival rates that approach 70%. However, for patients with
metastatic or relapsed osteosarcoma, there is currently no reliable therapeutic option to provide long-term tumor
control, emphasizing the urgent need for a better understanding of the disease.
In our efforts to unravel a potential role for the homeodomain protein TGIF in osteosarcoma pathogenesis
or progression, we undertook an in vivo mutagenesis approach using the Sleeping Beauty (SB) system. We
found that simultaneous deletion of the Tgif gene and activation of SB mutagenesis either in limb bud
mesenchymal cells or in committed osteoblasts culminated in the development of highly metastatic
osteosarcomas that display recurrent loss of p53 and p16Ink4a (p16), two suppressor genes frequently altered in
human osteosarcoma. Congruently, ectopic expression of TGIF suppressed proliferation of osteosarcoma cells
in a manner dependent on p53 and p16. To further dissect the functional interplay between TGIF and p53/p16,
we explored a physical interaction between TGIF and Twist1 that we identified in a yeast two hybrid screening,
because Twist1 has been shown to restrict both p53 and p16 expression, and more crucially, the Twist1 gene is
frequently amplified or overexpressed in human osteosarcoma. We found that TGIF associated with and
repressed Twist1 transcriptional activity, leading to p53 and p16 accumulation and an attendant suppression of
osteosarcoma cell proliferation. In human osteosarcoma, loss of TGIF expression, which is due in part to the
disruption of the TGIF gene, is associated with tumor aggressiveness, implicating TGIF as a potential
prognostic marker and possible target for attenuating deregulated cell proliferation in this malignancy.
Collectively, these findings prompted us to hypothesize that TGIF might function as a tumor suppressor in
osteosarcoma by antagonizing Twist1 expression and activity and thereby facilitating integration of the p53 and
p16 cytostatic programs. We also hypothesize that deregulated TGIF expression might be exploited to define a
signature to improve prognostic of osteosarcoma as well as to design innovative therapeutic strategies to curb
this lethal malignancy. These overarching hypotheses will be tested in the following specific aims: Aim 1:
Investigate the role of TGIF in osteosarcoma pathogenesis and progression, focusing on its functional
interaction with p53, p16, and Twsit1. Aim 2: Explore the mechanisms by which TGIF restrains osteosarcoma
progression, focusing on its ability to antagonize Twist1 expression and activity. Aim 3: Establish the clinical
relevance of deregulated TGIF expression in osteosarcoma. Comprehensive characterization of this newly
discovered tumor suppressor gene will likely open up new opportunities to the osteosarcoma field, both in terms
of delineating the underlying mechanisms, and in terms of prognosis and drug discovery.
总结
骨肉瘤是最常见的原发性骨恶性肿瘤,也是与癌症相关的第二大原因。
青少年死亡。在诊断时无明显转移的患者中,
辅助化疗的长期存活率接近70%。然而,对于患有
转移性或复发性骨肉瘤,目前没有可靠的治疗选择提供长期的肿瘤
控制,强调迫切需要更好地了解这种疾病。
在我们的努力,以解开一个潜在的作用,同源结构域蛋白TGIF在骨肉瘤发病机制
或进展,我们采用睡美人(SB)系统进行体内诱变方法。我们
发现Tgif基因的同时缺失和SB突变的激活,
间充质细胞或定向成骨细胞在高转移性骨肉瘤的发展中达到顶峰。
骨肉瘤显示p53和p16 Ink 4a(p16)的复发性丢失,这两种抑制基因在骨肉瘤中经常发生改变,
人骨肉瘤相应地,TGIF的异位表达抑制了骨肉瘤细胞的增殖
以依赖于p53和p16的方式。为了进一步分析TGIF和p53/p16之间的功能相互作用,
我们探索了我们在酵母双杂交筛选中鉴定的TGIF和Twist 1之间的物理相互作用,
因为Twist 1已被证明限制p53和p16的表达,更重要的是,Twist 1基因是
在人骨肉瘤中经常扩增或过表达。我们发现TGIF与
抑制Twist 1的转录活性,导致p53和p16的积累和随之而来的抑制,
骨肉瘤细胞增殖。在人骨肉瘤中,TGIF表达的缺失,部分是由于
TGIF基因的破坏与肿瘤的侵袭性有关,暗示TGIF是一种潜在的肿瘤抑制因子。
预后标志物和可能的目标衰减失调细胞增殖在这种恶性肿瘤。
总的来说,这些发现促使我们假设TGIF可能作为一种肿瘤抑制因子,
通过拮抗Twist 1的表达和活性,从而促进p53和
p16细胞抑制程序。我们还假设,TGIF表达的失调可能被用来定义一个新的基因。
改善骨肉瘤预后以及设计创新治疗策略
这种致命的恶性肿瘤将在以下具体目标中检验这些总体假设:目标1:
探讨TGIF在骨肉瘤发病机制和进展中的作用,
与p53、p16和Twsit 1相互作用。目的2:探讨TGIF抑制骨肉瘤的作用机制
进展,重点是其拮抗Twist 1表达和活性的能力。目标3:建立临床
骨肉瘤中TGIF表达失调的相关性全面描述这一新的
肿瘤抑制基因的发现将可能为骨肉瘤领域开辟新的机会,
描绘潜在的机制,以及预后和药物发现。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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{{ truncateString('Azeddine Atfi', 18)}}的其他基金
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10442384 - 财政年份:2020
- 资助金额:
$ 34.88万 - 项目类别:
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10174890 - 财政年份:2020
- 资助金额:
$ 34.88万 - 项目类别:
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10032715 - 财政年份:2020
- 资助金额:
$ 34.88万 - 项目类别:
Targeting Transglutaminase 2 in cancer cachexia
靶向转谷氨酰胺酶 2 治疗癌症恶病质
- 批准号:
10641967 - 财政年份:2020
- 资助金额:
$ 34.88万 - 项目类别:
Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
- 批准号:
10402355 - 财政年份:2019
- 资助金额:
$ 34.88万 - 项目类别:
Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
- 批准号:
9927610 - 财政年份:2019
- 资助金额:
$ 34.88万 - 项目类别:
Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
- 批准号:
10203885 - 财政年份:2019
- 资助金额:
$ 34.88万 - 项目类别:
Exploiting the Twist1 network in cancer cachexia
利用 Twist1 网络治疗癌症恶病质
- 批准号:
10629446 - 财政年份:2019
- 资助金额:
$ 34.88万 - 项目类别:
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