Organoid modeling to determine and reverse age-related epigenetic changes contributing to risk of colorectal cancer
用于确定和逆转导致结直肠癌风险的年龄相关表观遗传变化的类器官建模
基本信息
- 批准号:10657739
- 负责人:
- 金额:$ 40.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:APC mutationAccelerationAddressAffectAgeAgingAnimal TestingAutomobile DrivingAzacitidineBRAF geneBiological AssayBiological MarkersCRISPR/Cas technologyCellsCharacteristicsChronicClustered Regularly Interspaced Short Palindromic RepeatsColonColon CarcinomaColonic PolypsColorectal CancerCpG IslandsDNADNA MethylationDataDependenceDevelopmentDistalEngineeringEpigenetic ProcessEvolutionFeedbackFrequenciesGene ExpressionGene SilencingGenesGerm LinesGerm-Line MutationGrowthHistologicHumanHypermethylationIn VitroIndividualInflammatoryInflammatory Bowel DiseasesInterceptIntestinesKRAS oncogenesisKRAS2 geneLeftMalignant NeoplasmsMediatingMethylationModelingMonitorMucinousMusMutationOncogenicOrganoidsPathway interactionsPatientsPatternPhenotypePopulationPredispositionPreventionProcessRepressionRiskRisk FactorsRisk ReductionRoleSideStandardizationSyndromeSystemTestingTimeTumor PromotionWNT Signaling PathwayWorkage groupage relatedagedcancer initiationcancer predispositioncancer riskcancer subtypescell transformationcolorectal cancer preventioncolorectal cancer progressioncolorectal cancer riskcomplement pathwaydemethylationdisorder riskdriver mutationepigenetic therapyhigh riskin vivoindependencyinsightmouse modelmutantnormal agingnovelnovel strategiespharmacologicpolyposispre-clinicalpreventpromoterstemstem cellstumortumor progressiontumorigenesis
项目摘要
There is great need to develop systems in which the course for initiation and progression of cancer, and therapies
directed at these steps can be studied directly in mouse and human cells, and over time courses relevant to real
world tumorigenesis. While engineered mouse models are valuable, there is a need to develop complementary
systems where meaningful, relatively rapid in-vitro work can yield substantial pre-clinical insights leading to final
animal testing. In this regard, we have developed an organoid model which is yielding important data for studying
the age-related risks for developing colorectal cancer (CRC). The studies build on extensive data, now just in
press, derived from mouse organoids from normal proximal colon wherein we have modeled key steps in the
initiation and progression of CRC. The key findings are that despite the organoids being genetically stable over
time, they evolve an abnormal, gene promoter CpG island phenotype (CIMP) during long periods of growth. This
pattern is very similar to changes seen with aging in normal human colon and which parallels the increasing
CRC risk with age. CIMP involves repression of associated gene expression, and/or perhaps even more
importantly affects inducibility of genes which otherwise normally function in a feedback fashion to blunt abnormal
WNT and other stem pathway activation, prevent abnormal retention of cell renewal, and induce differentiation.
In this context, induction of Braf mutations in the older versus younger organoids result in a much more rapid
evolution of autonomous Wnt pathway activation, stem cell versus differentiation features and one-step
transformation by oncogenic Braf. The resulting cancers have typical histologic features and the epigenetic
abnormality of CIMP resembling oncogenic BRAF-driven human proximal colon CRCs. Critically, CRISPR-
mediated simultaneous inactivation of multiple CIMP target genes in young organoids rapidly converts these to
the old organoid phenotype, importantly resulting in rapid one-step transformation by oncogenic Braf. In the
current proposal, we will determine the role of genes affected by age-related CIMP in driving human CRC in the
context of KRAS, BRAF and APC mutations, thus addressing the epigenetic dependency of ~75% of CRC
evolution. This includes extrapolating our studies to human colon organoids. Importantly, our unique models
provide a novel setting to test whether epigenetic therapies can alter the above evolution of CIMP to suppress
age-related changes, which may otherwise enhance CRC risk. Results from these studies may allow insights for
strategies to prevent and/or intercept CRC evolution.
All of the work in our proposal has potential to define management strategies for CRC prevention and
interception, which could prove especially valuable for decreasing CRC risk in individuals harboring familial germ
line predisposition to colon polyps and for patients with inflammatory bowel diseases.
非常需要开发系统,其中癌症的起始和进展过程以及治疗方法
直接在小鼠和人类细胞中进行研究,随着时间的推移,
世界肿瘤发生。虽然工程小鼠模型是有价值的,但需要开发互补的
有意义的、相对快速的体外工作可以产生大量临床前见解的系统,
动物实验在这方面,我们已经开发了一个类器官模型,为研究提供了重要数据。
与年龄相关的结直肠癌(CRC)风险。这些研究建立在广泛的数据基础上,
Press,来源于正常近端结肠的小鼠类器官,其中我们模拟了
CRC的发生和发展。关键的发现是,尽管类器官在基因上是稳定的,
同时,它们在长时间的生长过程中进化出一种异常的基因启动子CpG岛表型(CIMP)。这
这种模式与正常人结肠中随年龄增长而发生的变化非常相似,
CRC风险随年龄增长。CIMP涉及相关基因表达的抑制,和/或甚至更多。
重要地影响基因的诱导,否则这些基因通常以反馈方式起作用,以钝化异常的
WNT等干细胞通路活化,阻止异常滞留细胞更新,并诱导分化。
在这种情况下,在较老的类器官中诱导Braf突变与在较年轻的类器官中诱导Braf突变相比,导致更快速的免疫应答。
自主Wnt通路激活的演变,干细胞与分化特征和一步
通过致癌的Braf转化。由此产生的癌症具有典型的组织学特征和表观遗传特征。
CIMP异常类似于致癌BRAF驱动的人近端结肠CRC。CRISPR-
在年轻的类器官中介导的多个CIMP靶基因的同时失活迅速将这些转化为
旧的类器官表型,重要的是导致致癌Braf的快速一步转化。在
目前的建议,我们将确定受年龄相关的CIMP影响的基因在驱动人类CRC中的作用,
KRAS、BRAF和APC突变的背景,从而解决了约75%的CRC的表观遗传依赖性
进化这包括将我们的研究外推到人类结肠类器官。重要的是,我们独特的模型
提供了一种新的设置,以测试表观遗传疗法是否可以改变CIMP的上述演变,以抑制
年龄相关的变化,这可能会增加CRC风险。这些研究的结果可能有助于了解
防止和/或拦截CRC演变的策略。
我们提案中的所有工作都有可能确定CRC预防的管理策略,
拦截,这可能被证明对于降低携带家族性细菌的个体的CRC风险特别有价值
结肠息肉和炎症性肠病患者的线易感性。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Combining EZH2 and HDAC inhibitors to target castration-resistant prostate cancers.
- DOI:10.1371/journal.pbio.3002081
- 发表时间:2023-04
- 期刊:
- 影响因子:9.8
- 作者:Coulter, Jonathan B.;Easwaran, Hariharan
- 通讯作者:Easwaran, Hariharan
Genetic and epigenetic dependencies in colorectal cancer development.
- DOI:10.1093/gastro/goac035
- 发表时间:2022
- 期刊:
- 影响因子:3.6
- 作者:Parmar, Sehej;Easwaran, Hariharan
- 通讯作者:Easwaran, Hariharan
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STEPHEN B. BAYLIN其他文献
STEPHEN B. BAYLIN的其他文献
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{{ truncateString('STEPHEN B. BAYLIN', 18)}}的其他基金
Organoid modeling to determine and reverse age-related epigenetic changes contributing to risk of colorectal cancer
用于确定和逆转导致结直肠癌风险的年龄相关表观遗传变化的类器官建模
- 批准号:
10206053 - 财政年份:2019
- 资助金额:
$ 40.72万 - 项目类别:
Characterizing age-associated epigenetic alterations and their roles in tumor development
表征与年龄相关的表观遗传改变及其在肿瘤发展中的作用
- 批准号:
9926803 - 财政年份:2019
- 资助金额:
$ 40.72万 - 项目类别:
Organoid modeling to determine and reverse age-related epigenetic changes contributing to risk of colorectal cancer
用于确定和逆转导致结直肠癌风险的年龄相关表观遗传变化的类器官建模
- 批准号:
10457265 - 财政年份:2019
- 资助金额:
$ 40.72万 - 项目类别:
(PQ4) - Tools for simultaneous disruption of multiple epigenetically silenced genes for studying their roles in tumorigenesis using ex vivo human and mouse colon organoid and in vivo mouse models
(PQ4) - 同时破坏多个表观遗传沉默基因的工具,用于使用离体人类和小鼠结肠类器官以及体内小鼠模型研究它们在肿瘤发生中的作用
- 批准号:
10471240 - 财政年份:2018
- 资助金额:
$ 40.72万 - 项目类别:
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