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High Mobility Group A1 Chromatin Regulators in Colon Carcinogenesis

结肠癌发生中的高迁移率 A1 组染色质调节因子

基本信息

批准号：
10599596
负责人：
Linda M S Resar
金额：
$ 11.39万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-24 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10599596
关键词：
ATAC-seq Adult Architecture Bacteria Cancer Etiology Cancer Model Cells Cessation of life Chromatin Chromatin Structure Clinical Colon Colon Carcinoma Colorectal Cancer Complex Country DNA Databases Development Distant Embryonic Development Epigenetic Process Epithelial Equilibrium Fostering Gene Expression Genes Genetic Genetic Transcription Homeostasis Human Incidence Inflammatory Knock-out Large Intestine Lead Link Malignant Neoplasms Mediating Modeling Molecular Mus Nature Non-Malignant Nuclear Oncogenic Organoids Outcome Paneth Cells Pathogenesis Pathway interactions Phenotype Pre-Clinical Model Property Proteins Role Signal Transduction Site Small Intestines Testing The Cancer Genome Atlas Tissues Transgenic Mice Treatment Efficacy WNT Signaling Pathway Woman Work adverse outcome base cancer stem cell carcinogenesis carcinogenicity chromatin remodeling colon carcinogenesis colon tumorigenesis men mouse model novel novel strategies novel therapeutic intervention overexpression parent grant polyposis postnatal pre-clinical premalignant prevent recruit replication factor C stem cell function stem cell niche stem cells therapeutic evaluation transcriptome sequencing tumor tumor progression

项目摘要

ABSTRACT & SPECIFIC AIMS (PARENT GRANT; score 4th%, Impact score – 2.0) Background: We propose to elucidate molecular mechanisms mediated by High Mobility Group A1 (HMGA1) chromatin remodeling proteins during colorectal carcinogenesis. The HMGA1 gene is highly expressed during embryogenesis, but silenced postnatally in most adult tissues. HMGA1 is also overexpressed in diverse, poorly differentiated cancers and high levels portend adverse outcomes. HMGA1 proteins modulate gene expression by “opening” chromatin and recruiting transcriptional complexes to DNA. While it is clear that chromatin regulators help to govern nuclear architecture and cell fate decisions, the underlying mechanisms are poorly understood. Here, we focus on HMGA1 in colorectal cancer (CRC). Our scientific premise that HMGA1 fosters tumor progression in CRC is based on the following preliminary results: 1) HMGA1 is highly overexpressed in CRC compared to non-malignant colonic epithelium, 2) Silencing HMGA1 blocks oncogenic properties, prevents metastatic progression, and depletes cancer stem cells in preclinical CRC models, 3) In transgenic mice, Hmga1 overexpression: a) induces hyperproliferation, aberrant crypt formation, and premalignant polyposis in small and large intestines, and, b) expands the small intestinal stem cell (ISC) pool by amplifying Wnt signals (Xian et al, Nature Comm; 2017), 5) Surprisingly, Hmga1 also helps to “build” a stem cell niche by inducing Sox9 to generate Paneth cells, which support and nurture small ISCs, 6) HMGA1 and SOX9 are positively correlated in human colon epithelium and both become markedly up- regulated in colon cancer, and, 7) Inflammatory signals and procarcinogenic bacteria associate with Hmga1 expression in preclinical tumor models. Together, these intriguing results support the following hypotheses: 1) Hmga1 is required for normal stem cell function and tissue homeostasis in colonic epithelium, 2) Deregulated HMGA1 disrupts this equilibrium and drives carcinogenesis and tumor progression through aberrant changes in chromatin structure and gene expression, 3) Inflammatory signals and specific pro-carcinogenic bacteria induce HMGA1 to drive tumor progession, and, 4) Identifying mechanisms linked to HMGA1 overexpression will reveal novel pathways that could be modulated to treat, or even prevent, colon carcinogenesis. Aims/Approach: To test this, we propose the following Specific Aims: 1) To define oncogenic and stem cell phenotypes dependent upon HMGA1 in colonic epithelium, 2) To elucidate epigenetic alterations and genetic pathways through which HMGA1 functions during carcinogenesis, and, 3) To determine whether targeting Hmga1 is effective in mitigating or preventing colon carcinogenesis in preclinical models. Impact: We expect to elucidate mechanisms that induce HMGA1 as well as downstream pathways governed by HMGA1 in CRC. This work could reveal a new paradigm for colon cancer pathogenesis and lead to novel approaches to treat, or even prevent, this formidable cancer. SPECIFIC AIMS (PARENT GRANT) 1) To determine how Hmga1 overexpression alters cell fate and proliferation in colonic epithelium during carcinogenesis. Here, we dissect the role of Hmga1 using our unique mouse and cell-based models. 2) To elucidate epigenetic alterations and molecular mechanisms through which HMGA1 functions during carcinogenesis. A) To test the hypothesis that Hmga1 promotes carcinogenesis by inducing Wnt genes and developmental transcriptional networks, we will integrate RNAseq, ChIPseq and ATACseq from colonic stem and progenitor cells with knock-out (KO), overexpression (OE), or wildtype (WT) Hmga1 in mouse models. B) To validate results in human colonic epithelium, we will interrogate TCGA databases and test the function of a subset of HMGA1 transcriptional target genes in human organoid models. 3) To test the therapeutic efficacy of targeting Hmga1 to prevent or mitigate tumor progression in preclinical models of CRC. Here, we compare colon tumorigenesis in mouse models + Hmga1 deficiency.

抽象和具体目标（PAYNET GRANT;得分4th%，影响得分- 2.0）背景：我们拟阐明高迁移率族A1介导的分子机制（HMGA 1）染色质重塑蛋白在结直肠癌发生过程中的作用。HMGA 1基因是一种高度在胚胎发育过程中表达，但在大多数成体组织中出生后沉默。HMGA 1也过表达在不同的、低分化的癌症中，高水平预示着不利的结果。HMGA 1蛋白调节通过“打开”染色质并将转录复合物募集到DNA来表达基因。虽然很明显染色质调节因子有助于控制核结构和细胞命运的决定，其潜在机制是不太了解。在这里，我们专注于HMGA 1在结直肠癌（CRC）。我们认为HMGA 1促进CRC肿瘤进展的科学前提是基于以下初步假设：结果：1）与非恶性结肠上皮相比，HMGA 1在CRC中高度过表达，2）沉默 HMGA 1阻断致癌特性，防止转移进展，并消耗肿瘤干细胞。 3）在转基因小鼠中，Hmga 1过表达：a）诱导过度增殖，异常增殖，小肠和大肠中的隐窝形成和癌前息肉病，和，B）扩张小肠 5）令人惊讶的是，Hmga 1还通过诱导Sox 9产生支持和培育小细胞的潘氏细胞，帮助“建立”干细胞生态位 ISCs，6）HMGA 1和SOX 9在人结肠上皮中呈正相关，并且两者在结肠上皮中均显著升高。在结肠癌中受到调节，以及，7）炎症信号和前致癌细菌与Hmga 1相关在临床前肿瘤模型中的表达。总之，这些有趣的结果支持以下假设：1）Hmga 1是正常干细胞所必需的 2）失调的HMGA 1破坏了这种平衡，通过染色质结构和基因的异常变化驱动癌发生和肿瘤进展表达，3）炎症信号和特异性促癌细菌诱导HMGA 1驱动肿瘤 4）识别与HMGA 1过表达相关的机制将揭示新的途径，可以调节以治疗甚至预防结肠癌的发生。目的/方法：为了验证这一点，我们提出了以下具体目的：1）定义致癌细胞和干细胞结肠上皮中依赖于HMGA 1的表型，2）为了阐明表观遗传改变和遗传学改变， HMGA 1在致癌过程中发挥作用的途径，以及，3）为了确定是否靶向在临床前模型中，hmga 1可有效减轻或预防结肠癌的发生。影响：我们希望阐明诱导HMGA 1以及下游途径的机制，在CRC中的HMGA 1。这项工作可以揭示结肠癌发病机制的新模式，并导致治疗甚至预防这种可怕癌症的新方法。具体目标（赠款） 1)为了确定Hmga 1过表达如何改变结肠上皮细胞的命运和增殖，致癌作用在这里，我们使用我们独特的小鼠和基于细胞的模型来剖析HMGA 1的作用。 2)阐明HMGA 1发挥功能的表观遗传学改变和分子机制在致癌过程中。A）检验Hmga 1通过诱导Wnt基因促进癌发生的假设和发育转录网络，我们将整合来自结肠茎的RNAseq、ChIPseq和ATACseq，和在小鼠模型中具有敲除（KO）、过表达（OE）或野生型（WT）Hmga 1的祖细胞。（B）为了验证在人类结肠上皮中的结果，我们将查询TCGA数据库，并测试一个人类类器官模型中HMGA 1转录靶基因的子集。 3)为了测试靶向Hmga 1以预防或减轻肿瘤进展的治疗功效， CRC的临床前模型。在这里，我们比较了结肠肿瘤发生在小鼠模型+Hmga 1缺陷。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic Engineering of Primary Mouse Intestinal Organoids Using Magnetic Nanoparticle Transduction Viral Vectors for Frozen Sectioning.

使用磁性纳米粒子转导病毒载体进行冷冻切片的原代小鼠肠类器官的基因工程。

DOI：
10.3791/57040
发表时间：
2019
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Xian,Lingling;Chia,Lionel;Georgess,Dan;Luo,Li;Shuai,Shuai;Ewald,AndrewJ;Resar,LindaMS
通讯作者：
Resar,LindaMS

High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer.

DOI：
10.1007/s10549-019-05419-1
发表时间：
2020-01
期刊：
BREAST CANCER RESEARCH AND TREATMENT
影响因子：
3.8
作者：
Gorbounov, Mikhail;Carleton, Neil M.;Asch-Kendrick, Rebecca J.;Xian, Lingling;Rooper, Lisa;Chia, Lionel;Cimino-Mathews, Ashley;Cope, Leslie;Meeker, Alan;Stearns, Vered;Veltri, Robert W.;Bae, Young Kyung;Resar, Linda M. S.
通讯作者：
Resar, Linda M. S.

Correction: Recent Developments and Therapeutic Strategies against Hepatocellular Carcinoma.

更正：肝细胞癌的最新进展和治疗策略。

DOI：
10.1158/0008-5472.can-19-2958
发表时间：
2019
期刊：
Cancer research
影响因子：
11.2
作者：
Yarchoan,Mark;Agarwal,Parul;Villanueva,Augusto;Rao,Shuyun;Dawson,Laura;Karasic,Thomas;Llovet,Joseph;Finn,Richard;Groopman,John;El-Serag,Hashem;Monga,Satdarshan;Wang,XinWei;Karin,Michael;Schwartz,Robert;Tanabe,Kenneth;Roberts
通讯作者：
Roberts

Doubling up on function: dual-specificity tyrosine-regulated kinase 1A (DYRK1A) in B cell acute lymphoblastic leukemia.

功能加倍：B 细胞急性淋巴细胞白血病中的双特异性酪氨酸调节激酶 1A (DYRK1A)。