Heterogeneous Loss of GDF11 Tumor Suppression in Triple-negative Breast Cancer

三阴性乳腺癌中 GDF11 肿瘤抑制的异质性缺失

基本信息

批准号：
10314040
负责人：
Kevin A Janes
金额：
$ 35.29万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2018-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10314040
关键词：
3-Dimensional Acinus organ component Adopted Alveolus Architecture Archives Attention BRCA1 gene Back Basement membrane Breast Breast Cancer Cell Breast Epithelial Cells Carcinoma Catalogs Categories Cells Cellular biology Cellularity Cessation of life Clinical Cues DNA DNA Repair DNA sequencing Differentiation and Growth Diffuse Disease Distant Drug resistance ERBB2 gene Equipment and supply inventories Evaluation Evolution Excision Extracellular Matrix Family GDF11 gene Genetic Genetic Transcription Genetically Engineered Mouse Genome Genomic Instability Genomics Goals Growth Hand Heterogeneity Histologic Hormone Receptor Hormones Human In Situ Lesion Ligands Liver Lobular Lung Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Mediating Methods Molecular Mutagenesis Mutation Neoplasms Organ Organoids Pathway interactions Pattern Phenotype Prognosis Property Proprotein Convertases Proteins Receptor Signaling Recombinants Regulation Research Resistance Shapes Signal Pathway Signal Transduction TP53 gene The Cancer Genome Atlas Tissues Transcript Transcription Repressor Transforming Growth Factor beta Tumor Cell Biology Tumor Suppression Tumor Suppressor Proteins Work aggressive breast cancer autocrine base breast cancer progression cancer type deep sequencing immunocytochemistry improved in vivo loss of function malignant breast neoplasm mammary epithelium molecular subtypes morphogens non-genetic novel novel therapeutics programs receptor expression skeletal targeted treatment three dimensional cell culture triple-negative invasive breast carcinoma tumor tumor initiation tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Roughly 85% of triple-negative breast cancers are categorized as basal-like or claudin-low carcinoma, molecular subtypes with especially poor prognosis and limited treatment options. Triple-negative breast cancers frequently harbor mutations in DNA-surveillance pathways; consequently, their overall genomic heterogeneity has been extensively characterized. By comparison, much less work has been done on the cell biology of triple-negative breast cancer. Despite the recognized histological nonuniformity of triple-negative tumors, we have only a rudimentary inventory of the types of signaling and transcriptional regulatory states that single basal-like and claudin-low cells can adopt. The long-term goal of this work is to identify and characterize the major cell-to-cell regulatory heterogeneities in triple-negative breast cancer. The current application focuses on growth-differentiation factor 11 (GDF11), a diffusible factor that is heterogeneously regulated in 3D organotypic cultures of claudin-low breast epithelial cells. Functional GDF11 bioactivity is lost in clinical cases of advanced triple-negative breast cancer, and addition of GDF11 to invasive claudin-low and basal-like cancer lines strongly suppresses invasion into basement membrane ECM. The hypothesis is that GDF11 acts a local breast-epithelial cue for proper lobular architecture, which is suppressed nongenetically during triple-negative breast cancer progression. The aims of this proposal are: 1) To identify the signaling and transcriptional mechanisms that mediate GDF11-induced phenotypes in triple-negative breast cancer. 2) To define the key steps of GDF11 misregulation in triple-negative neoplasms. 3) To determine the impact of GDF11 on progression and metastatic colonization of triple-negative tumors. The diversity of regulatory states enables triple-negative breast cancer cells to switch and adapt rapidly during tumor progression and the evolution of drug resistance. A complete inventory of regulatory states and their transitions could one day be harnessed by novel therapies that reset intratumor regulatory heterogeneity to delay progression or resistance.

项目概要/摘要大约 85% 的三阴性乳腺癌被归类为基底样癌或密蛋白低癌，预后特别差且治疗选择有限的分子亚型。三阴性乳腺癌症经常在 DNA 监视途径中存在突变；因此，他们的整体基因组异质性已被广泛表征。相比之下，在电池上所做的工作要少得多三阴性乳腺癌的生物学。尽管公认的三阴性组织学不均匀性对于肿瘤，我们只有信号传导类型和转录调控状态的基本清单单个basal-like和claudin-low细胞可以采用。这项工作的长期目标是识别和表征三阴性乳腺癌中主要的细胞间调控异质性。当前应用重点关注生长分化因子 11 (GDF11)，这是一种在 3D 中受到异质调节的扩散因子低密蛋白乳腺上皮细胞的器官型培养物。临床病例中功能性 GDF11 生物活性丧失晚期三阴性乳腺癌，以及将 GDF11 添加到侵袭性密蛋白低和基底样癌中线强烈抑制侵入基底膜 ECM。假设 GDF11 充当局部乳腺上皮提示适当的小叶结构，在三阴性期间受到非遗传性抑制乳腺癌进展。该提案的目的是：1）确定信号传导和转录介导三阴性乳腺癌中 GDF11 诱导表型的机制。 2）定义密钥三阴性肿瘤中 GDF11 失调的步骤。 3) 确定GDF11对三阴性肿瘤的进展和转移定植。监管国家的多样性使得三阴性乳腺癌细胞在肿瘤进展和进化过程中快速切换和适应耐药性。有一天，监管状态及其转变的完整清单可能会被利用重置肿瘤内调节异质性以延缓进展或耐药的新疗法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CIRCOAST: a statistical hypothesis test for cellular colocalization with network structures.

DOI：
10.1093/bioinformatics/bty638
发表时间：
2019-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
0
作者：
Corliss BA;Ray HC;Patrie JT;Mansour J;Kesting S;Park JH;Rohde G;Yates PA;Janes KA;Peirce SM
通讯作者：
Peirce SM