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:10206053
- 负责人:
- 金额:$ 24.08万
- 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 mutationAddressAffectAgeAgingAnimal 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 interactionsPatientsPatternPharmacologyPhenotypePopulationPredispositionPreventionProcessRepressionRiskRisk FactorsRoleSideStandardizationSyndromeSystemTestingTimeWNT Signaling PathwayWorkage groupage relatedagedcancer initiationcancer predispositioncancer riskcancer subtypescancer therapycell transformationcolorectal cancer preventioncolorectal cancer progressioncolorectal cancer riskcomplement pathwaydisorder riskdriver mutationepigenetic therapyhigh riskin vivoindependencyinsightmouse modelmutantnormal agingnovelnovel strategiespolyposispre-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.
非常需要开发癌症开始和进展的系统,以及疗法
针对这些步骤,可以直接在小鼠和人类细胞中研究,并且随着时间的流逝,与真实的课程有关
世界肿瘤发生。虽然工程鼠标的模型很有价值,但有必要发展互补
有意义的,相对较快的体内工作可以产生大量临床前见解的系统,导致最终见解
动物测试。在这方面,我们开发了一个类器官模型,该模型正在产生重要的数据
与年龄有关的结直肠癌(CRC)的风险。这些研究基于广泛的数据,现在只是
按下,源自从正常结肠的小鼠器官衍生的,其中我们已经建模了关键步骤
CRC的启动和进展。关键发现是,尽管有基因稳定的器官
时间,他们在长期生长的情况下进化了异常的基因启动子CpG岛表型(CIMP)。这
模式与正常人类结肠衰老的变化非常相似,并且与增加相似
CRC风险随着年龄的增长。 CIMP涉及对相关基因表达的抑制和/或更多
重要的是影响基因的诱导性,这些基因通常通常以反馈方式发挥作用
Wnt和其他茎途径激活,防止细胞更新异常保留,并诱导分化。
在这种情况下,诱导BRAF突变在较旧的类和年轻的类器官中会导致更快
自主Wnt途径激活,干细胞与分化特征的演变和一步
致癌BRAF的转化。由此产生的癌症具有典型的组织学特征和表观遗传学特征
CIMP异常类似于致癌BRAF驱动的人近端结肠CRC。批判性,crispr-
在年轻类器官中介导的多个CIMP靶基因的介导的同时失活,将其迅速转化为
旧的器官表型,重要的是导致致癌BRAF快速转变。在
当前的提案,我们将确定受年龄相关CIMP影响的基因在驱动人CRC中的作用
KRAS,BRAF和APC突变的背景,因此解决了约75%CRC的表观依赖性
进化。这包括将我们的研究推送到人类结肠器官。重要的是,我们独特的模型
提供一个新颖的设置,以测试表观遗传疗法是否可以改变CIMP的上述演变以抑制
与年龄相关的变化,否则可能会增强CRC风险。这些研究的结果可能可以洞悉
预防和/或拦截CRC进化的策略。
我们提案中的所有工作都有可能定义预防CRC的管理策略和
拦截,这可能证明对于降低携带家族性细菌的人的CRC风险特别有价值
对结肠息肉和炎症性肠病患者的倾向。
项目成果
期刊论文数量(0)
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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
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:
$ 24.08万 - 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:
10657739 - 财政年份:2019
- 资助金额:
$ 24.08万 - 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:
$ 24.08万 - 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:
$ 24.08万 - 项目类别:
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