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Defining the role of SWI/SNF chromatin remodeling complex mutations during melanoma progression

定义 SWI/SNF 染色质重塑复合体突变在黑色素瘤进展过程中的作用

基本信息

批准号：
10468456
负责人：
Alan Hunter Shain
金额：
$ 5.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2018-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468456
关键词：
Affect Applications Grants Award Biochemical Biological Biological Assay Biology CRISPR/Cas technology Cell Line Cells Cellular biology Chromatin Remodeling Factor Data Drosophila snf protein Drug Targeting Engineering Evolution Frequencies Future Genes Genetic Genetic Models Genetic Transcription Genetic study Genomics Goals Grant Homeostasis Human Infrastructure Intervention K22 Award Laboratories Lesion Malignant Neoplasms Mutate Mutation Normal tissue morphology Nucleosomes Patients Phenotype Process Publications Reproducibility Research Resources Role SWI/SNF Family Complex Secure Sucrose TP53 gene Testing Therapeutic Time Training Tumor Biology Tumor Suppressor Proteins base career career development chromatin remodeling daughter cell drug candidate gene function genetic approach genetic resource innovation melanocyte melanoma melanomagenesis migration mutant novel skills success tool tumor

项目摘要

Project Summary/Abstract The human SWItch/Sucrose NonFermentable chromatin-remodeling complex, commonly abbreviated as SWI/SNF, is composed of 10-15 biochemically distinct subunits. SWI/SNF complexes use the energy provided from ATP to reposition nucleosomes and modulate transcription. We found that SWI/SNF chromatin- remodeling genes are mutated in 20% of all cancers, including 30% of melanomas. While genetic studies clearly implicate SWI/SNF genes as tumor suppressors, it is not clear how mutations in these genes contribute to cancer. Experimental evidence from our group and others indicates that the genetic context in which a SWI/SNF component is perturbed heavily influences the fate of that cell. It will be important to study these mutations in their proper genetic context in order to resolve their functional contributions to cancer. Unfortunately, the genetic context in which SWI/SNF mutations occur is poorly understood. This is because tumors evolve through a multistep process, and most tumors are sequenced at a late stage, after they have fully evolved. I have developed an assay to determine the order of mutations as they occur during the evolution of melanoma. In aim 1 will utilize this assay to determine the precise context in which SWI/SNF mutations occur during the evolution of melanoma. This is innovative because I utilize a cutting-edge approach to reveal an unresolved feature of SWI/SNF tumor biology. In aim 2, I will engineer primary human melanocytes using CRISPR/Cas9 to mimic the genetic context prior to and after a SWI/SNF mutation occurs. These parental and SWI/SNF-mutant daughter cell lines will then be compared to functionally and mechanistically interrogate the effects of SWI/SNF mutations in an otherwise isogenetic background. This strategy is innovative because there are no known cell lines that definitively recapitulate the genetic context of a partially evolved melanoma before and after a SWI/SNF mutation occurs. I hypothesize that SWI/SNF mutations occur in a reproducible context during melanoma progression and promote either an invasive or a mutator phenotype. This hypothesis is based on observations from preliminary data that SWI/SNF mutations occur at the transition to invasive melanoma and coincide with a spike in the overall mutation burden. This proposal is significant because SWI/SNF genes are frequently mutated in melanoma, yet almost nothing is known regarding their roles in melanomagenesis. SWI/SNF proteins are not themselves ideal drug targets because they are tumor suppressors and are also important in normal cellular biology; however, completion of these studies should reveal the mechanisms underlying SWI/SNF melanoma biology and thus provide therapeutic opportunities for the large number of patients whose tumors are driven by these mutations. Finally, the protected time associated with this unique award mechanism will allow me to carry out scientific and professional career development activities, as described, that will facilitate the success of my independent research career.

项目总结/摘要人SWITCH/Sucrose NonFermentable染色质重塑复合物，通常缩写为 SWI/SNF由10-15个生物化学上不同的亚基组成。SWI/SNF复合体使用所提供的能量重新定位核小体并调节转录。我们发现SWI/SNF染色质- 重塑基因在20%的癌症中发生突变，包括30%的黑色素瘤。虽然基因研究虽然SWI/SNF基因可能是肿瘤抑制基因，但尚不清楚这些基因的突变如何影响肿瘤的发生，到癌症我们小组和其他人的实验证据表明， SWI/SNF组分的扰动严重影响该细胞的命运。研究这些将是重要的突变在其适当的遗传背景下，以解决其对癌症的功能贡献。不幸的是，SWI/SNF突变发生的遗传背景知之甚少。这是因为肿瘤通过多步骤的过程进化，并且大多数肿瘤在晚期阶段被测序，在它们已经完全进化。我发明了一种检测方法来确定进化过程中发生的突变顺序黑色素瘤在目的1中，将利用该测定来确定SWI/SNF突变的精确背景。发生在黑色素瘤的发展过程中。这是创新的，因为我利用尖端的方法来揭示 SWI/SNF肿瘤生物学的未解决特征。在目标2中，我将使用 CRISPR/Cas9模拟SWI/SNF突变发生之前和之后的遗传背景。这些父母和然后将比较SWI/SNF突变体子细胞系，以在功能上和机制上询问SWI/SNF突变体子细胞系。 SWI/SNF突变在其他同基因背景中的影响。这一战略具有创新性，因为没有已知的细胞系可以明确地概括部分进化的黑色素瘤的遗传背景，并且在SWI/SNF突变发生之后。我假设SWI/SNF突变发生在一个可重复的背景下，在黑色素瘤进展过程中并促进侵袭性或突变表型。这种假设是基于对初步数据的观察，SWI/SNF突变发生在向侵袭性转移时，黑色素瘤，并符合在整体突变负荷的峰值。这一建议意义重大，因为 SWI/SNF基因在黑色素瘤中经常发生突变，但关于它们在黑色素瘤中的作用几乎一无所知。黑色素瘤形成SWI/SNF蛋白本身不是理想的药物靶点，因为它们是肿瘤靶点，在正常细胞生物学中也很重要;然而，完成这些研究应揭示了SWI/SNF黑色素瘤生物学的潜在机制，从而为以下疾病提供治疗机会：大量患者的肿瘤是由这些突变引起的。最后，保护时间与这种独特的奖励机制将使我能够开展科学和专业的职业生涯发展活动，如所述，这将有助于我的独立研究生涯的成功。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Evolution of Melanoma - Moving beyond Binary Models of Genetic Progression.

黑色素瘤的进化 - 超越遗传进展的二元模型。

DOI：
10.1016/j.jid.2019.08.002
发表时间：
2020
期刊：
The Journal of investigative dermatology
影响因子：
0
作者：
Zeng,Hanlin;Judson-Torres,RobertL;Shain,AHunter
通讯作者：
Shain,AHunter

Two Trajectories to Melanoma on the Hands and Feet.

手和脚黑色素瘤的两条轨迹。

DOI：
10.1001/jamadermatol.2021.0792
发表时间：
2021
期刊：
JAMA dermatology
影响因子：
10.9
作者：
Shain,AHunter
通讯作者：
Shain,AHunter

Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution.

DOI：
10.1016/j.ccell.2018.06.005
发表时间：
2018-07-09
期刊：
Cancer cell
影响因子：
50.3
作者：
Shain AH;Joseph NM;Yu R;Benhamida J;Liu S;Prow T;Ruben B;North J;Pincus L;Yeh I;Judson R;Bastian BC
通讯作者：
Bastian BC

The landscape of driver mutations in cutaneous squamous cell carcinoma.