BRMS1-mediated suppression of metastases in p53 mutant lung adenocarcinoma

BRMS1 介导的 p53 突变肺腺癌转移抑制

• 批准号: 10308007
• 负责人: David R Jones
• 金额: $ 40.65万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308007
• 关键词: Adenocarcinoma Cell; BRMS1 gene; Binding; Biological Assay; Biological Models; Breast Cancer Prevention; CRISPR/Cas technology; Cells; ChIP-seq; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA Binding; DNA Binding Domain; DNA Sequence Alteration; Databases; Development; Down-Regulation; Elements; Epidermal Growth Factor Receptor; Future; Gene Chips; Gene Expression; Genes; Genetic Transcription; Genetically Engineered Mouse; Genomics; Goals; Histologic; Histology; Human; Innovative Therapy; KRASG12D; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mesenchymal; Metastasis Suppression; Metastasis Suppressor Genes; Modeling; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Organoids; Pathologic; Patients; Persons; Phenotype; Phosphorylation; Prognosis; Progression-Free Survivals; Promoter Regions; Recurrence; Reporter Genes; Research; Sampling; Secondary to; Solid; Specimen; System; TNF gene; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Transcriptional Regulation; United States; Work; base; biobank; cancer cell; cell motility; clinically relevant; efficacy evaluation; gene function; genome-wide; inducible gene expression; inhibitor; maspin; migration; mouse model; multicatalytic endopeptidase complex; mutant; novel; p65; promoter; restoration; small hairpin RNA; transcription factor; transcriptome sequencing; tumor

Metastatic lung cancer kills >180,000 people in the United States annually and only ~10% of patients with lung adenocarcinoma (LUAD) have targetable driver genomic alterations. There remains an unmet need for innovative therapies. BRMS1 is a metastasis suppressor gene that is decreased in LUAD and is associated with increased cancer migration, invasion, and poor prognosis. Mutations in DNA binding domain (DBD) of p53 are common in LUAD and are associated with increased metastases. We have made a novel observation that BRMS1 functions as transcription factor for selected metastasis-related genes in p53mut but not p53WT LUAD. Specifically, we show that BRMS1 binds promoter regions containing active p53 responsive elements to transcriptionally regulate metastasis-related genes, Maspin and Serpine1, in p53mut but not p53WT LUAD. Moreover, we demonstrate that BRMS1 expression is related to biologically distinct histologic subtypes of LUAD and that restoration of BRMS1 using the CK2 inhibitor CX4945 results in significantly less cell migration and invasion in p53mut compared with p53WT LUAD. Our overarching goal is to determine the importance of maintaining BRMS1 in the context of p53 mutations using clinically relevant, human LUAD samples, patient-derived organoids (PDO), and conditional GEMM models. Two Specific Aims will test our hypotheses: Aim 1) Identify downstream targets and associated components of BRMS1-mediated transcription in p53mut LUAD. We will use ChIP-seq to identify genome-wide specific BRMS1-DNA binding regions in p53mut LUAD cells. We will then determine the functional significance of BRMS1-DNA binding on transcriptional regulation by performing RNA-seq in BRMS1WT and BRMS1KO LUAD isogenic cells with different p53 status. Next, using shRNA screens combined with reporter gene assays to characterize gene-specific components, we test the hypothesis that BRMS1 differentially regulates transcription via interaction with unique transcription co-factors in p53mut LUAD. Aim 2) Determine the requirement for BRMS1 in regulating metastases in human p53mut LUAD. We will leverage our extensive, clinically-annotated biorepository of >2000 human LUAD specimens with varying p53 mutational profiles, pathologic stages, and histologic subtypes to characterize the spectrum of LUAD tumors. We then examine the efficacy of the CK2 inhibitor, CX4945, in preventing BRMS1 degradation and decreasing metastases in specific histological subtypes of LUAD using our newly developed LUAD patient-derived organoid (PDO) model of metastases. We use this PDO model modified with an inducible expression system to assess the importance of maspin, and serpine1 on BRMS1-mediated metastasis suppression. Finally, using our newly created Brms1-/-/KrasG12D GEMM with intratracheal delivery of p53mut CRISPR we create a metastatic LUAD mouse model to assess the requirement of BRMS1 for CX4945- mediated suppression of metastases. Impact: Our work will provide mechanistic and translational evidence to support future clinical trials that target BRMS1 in p53mut LUAD with biologically distinct histologic subtypes.

在美国，转移性肺癌每年导致> 180，000人死亡，并且只有约10%的肺癌患者 腺癌（LUAD）具有可靶向的驱动基因组改变。仍然有一个未满足的需要， 创新疗法BRMS 1是一种转移抑制基因，在LUAD中减少， 增加了癌症的迁移、侵袭和不良预后。p53基因DNA结合域（DBD）突变 在LUAD中很常见，并与转移增加相关。我们做出了一个新颖的观察 BRMS 1在p53 mut中作为选择的转移相关基因的转录因子发挥作用， p53WT LUAD.具体地说，我们发现BRMS 1结合启动子区含有活性p53反应， p53 mut中转录调节转移相关基因Maspin和Serpine 1的元件，但不调节p53 WT LUAD。此外，我们证明BRMS 1表达与生物学上不同的组织学亚型有关， 使用CK 2抑制剂CX 4945恢复BRMS 1导致显著减少的细胞数量， 与p53 WT LUAD相比，p53 mut的迁移和侵袭。我们的首要目标是确定 使用临床相关的人LUAD在p53突变背景下维持BRMS 1的重要性 样本、患者源性类器官（PDO）和条件性GEMM模型。两个具体目标将考验我们的 假设：目的1）鉴定BRMS 1介导的转录的下游靶点和相关组分 在p53 mut LUAD中。我们将使用ChIP-seq来鉴定p53 mut中全基因组特异性BRMS 1-DNA结合区域， LUAD细胞。然后，我们将确定BRMS 1-DNA结合在转录水平上的功能意义。 通过在具有不同p53状态的BRMS 1 WT和BRMS 1 KO LUAD同基因细胞中进行RNA-seq来调节。 接下来，使用与报告基因测定相结合的shRNA筛选来表征基因特异性组分， 我们检验了BRMS 1通过与独特的转录相互作用来差异调节转录的假设， p53 mut LUAD中的辅助因子。目的2）确定BRMS 1在调节人类转移中的需求 p53mut LUAD.我们将利用我们广泛的，临床注释的生物储存库>2000人LUAD 具有不同p53突变谱、病理分期和组织学亚型的标本，以表征 LUAD肿瘤谱。然后，我们研究了CK 2抑制剂CX 4945在预防BRMS 1 在LUAD的特定组织学亚型中，使用我们新开发的 LUAD患者来源的类器官（PDO）转移模型。我们使用这个PDO模型， 诱导表达系统，以评估maspin和serpine 1对BRMS 1介导的 转移抑制最后，使用我们新创建的Brms 1-/-/KrasG 12 D GEMM， p53 mut CRISPR我们创建了转移性LUAD小鼠模型以评估BRMS 1对CX4945的需求。 介导的转移抑制。影响：我们的工作将提供机械和翻译证据， 支持未来针对具有生物学不同组织学亚型的p53 mut LUAD中BRMS 1的临床试验。

项目成果

Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.

• DOI: 10.1016/j.ccell.2021.09.008
• 发表时间: 2021-11-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Chan JM;Quintanal-Villalonga Á;Gao VR;Xie Y;Allaj V;Chaudhary O;Masilionis I;Egger J;Chow A;Walle T;Mattar M;Yarlagadda DVK;Wang JL;Uddin F;Offin M;Ciampricotti M;Qeriqi B;Bahr A;de Stanchina E;Bhanot UK;Lai WV;Bott MJ;Jones DR;Ruiz A;Baine MK;Li Y;Rekhtman N;Poirier JT;Nawy T;Sen T;Mazutis L;Hollmann TJ;Pe'er D;Rudin CM
• 通讯作者: Rudin CM

A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab.

• DOI: 10.1158/2159-8290.cd-21-0407
• 发表时间: 2021-11
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Adusumilli PS;Zauderer MG;Rivière I;Solomon SB;Rusch VW;O'Cearbhaill RE;Zhu A;Cheema W;Chintala NK;Halton E;Pineda J;Perez-Johnston R;Tan KS;Daly B;Araujo Filho JA;Ngai D;McGee E;Vincent A;Diamonte C;Sauter JL;Modi S;Sikder D;Senechal B;Wang X;Travis WD;Gönen M;Rudin CM;Brentjens RJ;Jones DR;Sadelain M
• 通讯作者: Sadelain M

Expansion of the Concept of Micropapillary Adenocarcinoma to Include a Newly Recognized Filigree Pattern as Well as the Classical Pattern Based on 1468 Stage I Lung Adenocarcinomas.

• DOI: 10.1016/j.jtho.2019.07.008
• 发表时间: 2019-11
• 期刊: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
• 作者: Emoto K;Eguchi T;Tan KS;Takahashi Y;Aly RG;Rekhtman N;Travis WD;Adusumilli PS
• 通讯作者: Adusumilli PS

Minimally Invasive Lobectomy Is Associated With Lower Noncancer-specific Mortality in Elderly Patients: A Propensity Score Matched Competing Risks Analysis.

• DOI: 10.1097/sla.0000000000002772
• 发表时间: 2019-12
• 期刊: Annals of surgery
• 影响因子: 9
• 作者: Hristov B;Eguchi T;Bains S;Dycoco J;Tan KS;Isbell JM;Park BJ;Jones DR;Adusumilli PS
• 通讯作者: Adusumilli PS

Thoracic Metastasectomy in Germ Cell Tumor Patients Treated With First-line Versus Salvage Therapy.

• DOI: 10.1016/j.athoracsur.2020.06.072
• 发表时间: 2021-04
• 期刊: The Annals of thoracic surgery
• 作者: Caso R;Jones GD;Tan KS;Bosl GJ;Funt SA;Sheinfeld J;Reuter VE;Amar D;Fischer G;Molena D;Rocco G;Bains MS;Feldman DR;Jones DR
• 通讯作者: Jones DR