Molecular origins and impact of APOBEC3 mutagenesis in cancer
APOBEC3 突变的分子起源和对癌症的影响
基本信息
- 批准号:10693177
- 负责人:
- 金额:$ 40.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressB-Cell LymphomasBioinformaticsBiological AssayBiological MarkersBiological ModelsBreast Cancer cell lineCancer EtiologyCancer ModelCancer cell lineCell LineCell modelCellsCharacteristicsClinicalCytidineCytosine deaminaseDataDeaminaseDetectionDimensionsDiseaseEngineeringEnzymesEtiologyEvolutionExposure toFamilyGene MutationGenomeGoalsHigh PrevalenceHumanImmuneIndividualKnock-outLinkLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of urinary bladderMeasuresMetastatic CarcinomaModelingMolecularMonitorMusMutagenesisMutationMutation AnalysisNeoplasm MetastasisOutcomePatient SelectionPatternPhysiologicalPlayPolymeraseProcessRNA VirusesReagentRegulationResistanceRetroelementsRodentRoleSensitivity and SpecificitySingle base substitutionSingle-Stranded DNASiteSourceSurrogate MarkersSystemTestingTherapeuticTransgenesTreatment EfficacyTyrosine Kinase InhibitorXenograft procedurebiomarker validationcancer cellcancer genomecancer preventioncancer therapycancer typecarcinogenesisexperimental studygenome sequencinghuman diseaseimprintinsightlung cancer cellmalignant breast neoplasmmembermutantnovel strategiesoverexpressionparalogous genepreferenceprognosticreconstitutionrecruitscaffoldtargeted treatmenttherapeutic targettherapy resistanttumorigenesiswhole genome
项目摘要
PROJECT SUMMARY
Mutations arise as a result of exogenous and endogenous processes that leave characteristic imprints or
signatures upon the genome. Systematic analysis of these mutational signatures led to the identification of >50
distinct types of single base substitutions (SBS) in human cancer genomes. Revealing the origins of individual
signatures is critical for understanding cancer etiology, with potential implications for cancer prevention and
therapy. Two of the most prevalent mutational signatures in cancer, termed SBS2 and SBS13, are present in
>78% of cancer types and 56% of all cancer genomes, with a particular prominence in breast, bladder, and
lung cancers. SBS2 and SBS13 are proposed to be caused by the endogenous APOBEC3 (A3) enzymes,
which target ssDNA and RNA of viruses and retroelements as part of the innate immune defense. Correlations
between A3 expression, driver gene mutations in A3-preferred contexts, and clinical outcomes suggest that A3
mutagenesis may play important roles in cancer etiology and evolution. Thus, there is strong rationale to
understand the mechanisms of A3 activity. However, reliance on engineered model systems and correlative
data have caused links between A3 enzymes, mutations in cancer, and cancer etiology to be poorly
understood. We have identified human cancer cell lines with endogenous A3 mutagenesis and developed a
workflow that enables us to quantify contributions of individual A3 members to mutations. Here, we propose to
leverage this workflow to accomplish the following goals: 1) Identify A3 mutator enzymes in cancer types where
A3 mutagenesis is prevalent and find biomarkers of their activity; 2) Investigate mechanisms modulating A3
mutagenesis; 3) Determine the functional relevance of A3 mutagenesis in therapy resistance and metastasis.
Aim 1 will expand upon our characterization of human cancer cells with active A3 mutagenesis to identify A3
mutators in breast, bladder, and lung cancers. In parallel, we will directly assess the unknown specificity and
sensitivity of assays to measure activities of individual A3 enzymes. These experiments may further confirm
the speculative A3-etiology of a large number of cancer mutations and quantify contributions of individual A3
enzymes, thus nominating them as putative targets for therapeutic pursuit. Aim 2 builds on our preliminary data
to investigate proposed modulators of A3 mutagenesis. These experiments have the potential to broaden the
scope of therapeutic opportunities focused on cancer cell evolution. Aim 3 will assess the links between A3
enzymes, therapy resistance and metastasis in breast, bladder, and lung cancer cell lines. These experiments
will test predictions from multi-dimensional associations that A3-mutagenesis is a disease-modifying process
that can be therapeutically exploited at various stages of cancer evolution. Taken together, these studies will
define the etiologies of highly prevalent mutational processes and identify strategies to elicit more durable
clinical benefits to targeted therapies and curb metastasis.
项目总结
突变是外源和内源过程的结果,这些过程留下了特有的印记或
基因组上的签名。对这些突变特征的系统分析导致了>;50的鉴定
人类癌症基因组中不同类型的单碱基替换(SBS)。揭示个体的起源
签名对于理解癌症病因学至关重要,对癌症预防和治疗具有潜在意义。
心理治疗。癌症中最常见的两个突变信号,称为SBS2和SBS13,存在于
78%的癌症类型和56%的癌症基因组,尤其是在乳腺癌、膀胱癌和
肺癌。SBS2和SBS13被认为是由内源性APOBEC3(A3)酶引起的,
它以病毒和逆转录元件的单链DNA和RNA为靶标,作为天然免疫防御的一部分。相关性
在A3表达、A3偏好背景下的驱动基因突变和临床结果之间的关系表明,A3
突变可能在肿瘤的病因学和进化中发挥重要作用。因此,有很强的理由
了解A3活性的机制。然而,依赖工程模型系统和相关
数据导致A3酶、癌症突变和癌症病因学之间的联系很差。
明白了。我们已经鉴定出具有内源性A3突变的人类癌细胞系,并开发出一种
使我们能够量化单个A3成员对突变的贡献的工作流程。在此,我们建议
利用此工作流程实现以下目标:1)确定癌症类型中的A3突变体酶
A3的诱变很普遍,并找到了它们活性的生物标志物;2)研究了A3的调节机制
3)确定A3突变在耐药和转移中的功能相关性。
Aim 1将扩展我们对具有活性A3突变的人类癌细胞的特征,以确定A3
乳腺癌、膀胱癌和肺癌中的突变者。同时,我们将直接评估未知的特异性和
测定单个A3酶活性的灵敏度。这些实验可能进一步证实
推测大量癌症突变的A3病因学并量化个体A3的贡献
酶,从而将它们指定为治疗追求的假定靶点。AIM 2以我们的初步数据为基础
研究已提出的A3诱变调节剂。这些实验有可能扩大
治疗机会的范围集中在癌细胞的进化上。目标3将评估A3和A3之间的联系
酶与乳腺癌、膀胱癌和肺癌细胞株的治疗耐药和转移。这些实验
将测试来自多维关联的预测,即3-突变是一个疾病修正过程
这一点可以在癌症进化的不同阶段用于治疗。总而言之,这些研究将
确定高度流行的突变过程的病因,并确定策略以获得更持久的
靶向治疗和抑制转移的临床益处。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JOHN MACIEJOWSKI其他文献
JOHN MACIEJOWSKI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JOHN MACIEJOWSKI', 18)}}的其他基金
Immune control and genomic instability at micronuclei
微核的免疫控制和基因组不稳定性
- 批准号:
10365554 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Immune control and genomic instability at micronuclei
微核的免疫控制和基因组不稳定性
- 批准号:
10544747 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
The origins of chromosome rearrangement in the cancer genome
癌症基因组中染色体重排的起源
- 批准号:
9352813 - 财政年份:2016
- 资助金额:
$ 40.94万 - 项目类别:
The origins of chromosome rearrangement in the cancer genome
癌症基因组中染色体重排的起源
- 批准号:
9223946 - 财政年份:2016
- 资助金额:
$ 40.94万 - 项目类别:
相似海外基金
Roles of immune cells derived from clonal hematopoiesis in B-cell lymphomas
克隆造血来源的免疫细胞在 B 细胞淋巴瘤中的作用
- 批准号:
24K19213 - 财政年份:2024
- 资助金额:
$ 40.94万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Identification of novel biomarkers for EBV-associated B-cell lymphomas arising in the oral cavity
口腔中出现的 EBV 相关 B 细胞淋巴瘤的新型生物标志物的鉴定
- 批准号:
23K15982 - 财政年份:2023
- 资助金额:
$ 40.94万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Chromunities Drive Transcriptional Reprogramming in Humoral Immunity and B-cell Lymphomas
染色体驱动体液免疫和 B 细胞淋巴瘤中的转录重编程
- 批准号:
10606730 - 财政年份:2023
- 资助金额:
$ 40.94万 - 项目类别:
Curing Through Collaboration: Utilizing Cooperative Groups in the Fight Against Chronic Lymphocytic Leukemia and B-cell Lymphomas
通过合作进行治愈:利用合作团体对抗慢性淋巴细胞白血病和 B 细胞淋巴瘤
- 批准号:
10566833 - 财政年份:2023
- 资助金额:
$ 40.94万 - 项目类别:
Curing Through Collaboration: Utilizing Cooperative Groups in the Fight Against Chronic Lymphocytic Leukemia and B-cell Lymphomas
通过合作进行治愈:利用合作团体对抗慢性淋巴细胞白血病和 B 细胞淋巴瘤
- 批准号:
10987699 - 财政年份:2023
- 资助金额:
$ 40.94万 - 项目类别:
Synthetic lethal targeting of EBV-positive diffuse large B cell lymphomas in persons living with HIV
HIV 感染者 EBV 阳性弥漫性大 B 细胞淋巴瘤的合成致死靶向
- 批准号:
10541285 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Role of Epstein-Barr virus LMP2A protein in maintaining oncogenic IgM signaling in EBV+ B cell lymphomas
Epstein-Barr病毒LMP2A蛋白在维持EBV B细胞淋巴瘤中致癌IgM信号传导中的作用
- 批准号:
10540952 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Synthetic lethal targeting of EBV-positive diffuse large B cell lymphomas in persons living with HIV
HIV 感染者 EBV 阳性弥漫性大 B 细胞淋巴瘤的合成致死靶向
- 批准号:
10703446 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Therapeutic potential of novel antibody-oligonucleotide conjugate for intractable B-cell lymphomas
新型抗体-寡核苷酸缀合物治疗难治性 B 细胞淋巴瘤的潜力
- 批准号:
22K08497 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Role of Epstein-Barr virus LMP2A protein in maintaining oncogenic IgM signaling in EBV+ B cell lymphomas
Epstein-Barr病毒LMP2A蛋白在维持EBV B细胞淋巴瘤中致癌IgM信号传导中的作用
- 批准号:
10707312 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别: