Omic and Multidimensional Spatial Atlas of Metastatic Breast Cancer

转移性乳腺癌的组学和多维空间图谱

• 批准号: 10818062
• 负责人: Emek Demir
• 金额: $ 92.33万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-04 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10818062
• 关键词: ATAC-seq; Acceleration; Aftercare; Atlases; Biological; Biological Assay; Biological Markers; Biological Process; Biopsy; Blood; Breast Cancer Treatment; CDK4 gene; Cells; Chromatin; Clinical; Collection; Communities; Core Biopsy; Coupled; DNA sequencing; Data; Data Analyses; Data Coordinating Center; Data Set; Development; Diagnostic Procedure; Dimensions; Electron Microscope; Evaluation; Formalin; Foundations; Freezing; Generations; Genomics; Goals; Heterogeneity; Image; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Immunohistochemistry; Ions; Malignant Neoplasms; Manuscripts; Maps; Metadata; Metastatic breast cancer; Molecular; Noninfiltrating Intraductal Carcinoma; Paraffin Embedding; Pathway interactions; Patients; Periodicity; Plant Resins; Poly(ADP-ribose) Polymerase Inhibitor; Publications; Resistance; Resource Sharing; Resources; Sampling; Scanning; Scientist; Specimen; Structure; Therapeutic; Three-Dimensional Image; Time; Tissues; Tumor-Derived; Visualization; Work; anticancer research; biological systems; cancer subtypes; cohort; data integration; data sharing; hormone receptor-positive; hormone therapy; immune checkpoint; immune modulating agents; individual patient; inhibitor; innovation; malignant breast neoplasm; multimodal data; multimodality; neoplastic cell; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; operation; paraform; programs; prospective; resistance mechanism; sample collection; success; targeted treatment; therapy resistant; tool; treatment response; triple-negative invasive breast carcinoma; tumor; tumor-immune system interactions

PROJECT ABSTRACT We will continue development of our Omic and Multidimensional Spatial (OMS) Atlas that enables discovery of mechanisms of resistance that arise in individual patients with metastatic breast cancer during treatment with current generation targeted therapeutic combinations and immune checkpoint inhibitors. The OMS Atlas is motivated by the fact that these treatments typically are only transiently effective in the metastatic setting. Possible resistance mechanisms may be intrinsic to the tumor cells or derive from the diverse microenvironments in which the tumor cells live. The OMS Atlas focuses on elucidating these resistance mechanisms in two current generation clinical scenarios: (a) hormone-receptor positive breast cancer (HRBC) undergoing treatment with a CDK4/6 inhibitor in combination with endocrine therapy, and (b) triple negative breast cancer (TNBC) undergoing treatment with a PARP inhibitor and an immunomodulatory agent. We are accomplishing this through work via four coordinated units. A Biospecimen Unit is prospectively collecting and distributing longitudinal clinical information, blood, and biopsies from 30 cases across the two metastatic breast cancer cohorts. A Characterization Unit is analyzing (a) OCT frozen specimens using single-cell DNA-seq and single-cell ATAC- seq to elucidate spatially defined genomic changes and chromatin accessibility in single cells, (b) formalin fixed, paraffin embedded (FFPE) specimens using multiplex immunohistochemistry (mIHC) to assess the immune microenvironment and cyclic Immunofluorescence (cycIF) to assess the composition and molecular states of tumor cells and their microenvironments, and (c) paraformaldehyde fixed, resin embedded (PFRE) specimens using a Focused Ion Beam Scanning Electron Microscope (FIB-SEM) to identify ultrastructural changes in 2D images and targeted 3D images. Omic characterization of the same tumor samples is provided by the SMMART Program. A Data Analysis Unit is developing and deploying tools to (a) manage, analyze, and visualize omics and imaging datasets, (b) integrate omics and imaging datasets through crosswise mapping to create single timepoint tumor maps and quantify systems biological functions of tumor cellular subpopulations, and (c) explore differences between pre- and on/post-treatment tumor maps to reveal mechanisms of resistance. The Administrative Unit facilitates the coordination, operation, interaction, and evaluation of activities within the OMS Atlas and between OMS Atlas scientists and the HTAN. In this project, we will complete our planned OMS Atlas project through the following Aims: (1) perform characterization of five additional patient cases using our omics and multiscale imaging assays; (2) upload our remaining datasets and metadata to the HTAN data coordinating center; and (3) perform integrated data analysis across our atlas case datasets as well as HTAN trans-network project datasets to identify tumor changes on therapy and the implications of those changes on breast cancer treatment. By accomplishing these aims we will complete and fully share our multimodal spatial atlas of 30 metastatic breast cancer cases undergoing treatment.

项目摘要 我们将继续开发我们的组学和多维空间 (OMS) 图集，以便发现 转移性乳腺癌个体患者在治疗过程中出现的耐药机制 当前一代靶向治疗组合和免疫检查点抑制剂。 OMS 图集是 其动机是这些治疗通常在转移性环境中仅短暂有效。 可能的耐药机制可能是肿瘤细胞固有的或源自不同的微环境 肿瘤细胞生活在其中。 OMS 图集重点阐述两种当前的耐药机制 生成临床情景：(a) 激素受体阳性乳腺癌 (HRBC) 正在接受治疗 CDK4/6 抑制剂联合内分泌治疗，以及 (b) 正在接受三阴性乳腺癌 (TNBC) 治疗的患者 使用 PARP 抑制剂和免疫调节剂进行治疗。我们正在通过工作来实现这一目标 四个协调单位。生物样本单位正在前瞻性地收集和分发纵向临床 来自两个转移性乳腺癌队列的 30 例病例的信息、血液和活检。一个 表征单元正在使用单细胞 DNA-seq 和单细胞 ATAC 分析 (a) OCT 冷冻样本 seq 阐明单细胞中空间定义的基因组变化和染色质可及性，(b) 福尔马林固定， 使用多重免疫组织化学 (mIHC) 石蜡包埋 (FFPE) 标本来评估免疫 微环境和循环免疫荧光（cycIF）来评估的组成和分子状态 肿瘤细胞及其微环境，以及 (c) 多聚甲醛固定、树脂包埋 (PFRE) 标本 使用聚焦离子束扫描电子显微镜 (FIB-SEM) 识别二维超微结构变化 图像和目标 3D 图像。 SMMART 提供相同肿瘤样本的组学表征 程序。数据分析部门正在开发和部署工具来 (a) 管理、分析和可视化组学 和成像数据集，（b）通过交叉映射整合组学和成像数据集以创建单个 时间点肿瘤图谱并量化肿瘤细胞亚群的系统生物学功能，以及（c）探索 治疗前和治疗中/治疗后肿瘤图之间的差异以揭示耐药机制。这 行政单元促进 OMS 内活动的协调、操作、交互和评估 Atlas 以及 OMS Atlas 科学家和 HTAN 之间的关系。在这个项目中，我们将完成我们计划的OMS Atlas 项目通过以下目标：（1）使用我们的组学对另外五个患者病例进行表征 和多尺度成像测定； (2) 将我们剩余的数据集和元数据上传到 HTAN 数据协调 中心; (3) 对我们的 Atlas 案例数据集以及 HTAN 跨网络进行综合数据分析 项目数据集以确定治疗中的肿瘤变化以及这些变化对乳腺癌的影响 治疗。通过实现这些目标，我们将完成并充分分享我们的 30 个多模式空间图集 正在接受治疗的转移性乳腺癌病例。

项目成果

Quality Control for Single Cell Analysis of High-plex Tissue Profiles using CyLinter.

使用 CyLinter 对高复合组织概况进行单细胞分析的质量控制。

• DOI: 10.1101/2023.11.01.565120
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Baker,GregoryJ;Novikov,Edward;Zhao,Ziyuan;Vallius,Tuulia;Davis,JanaeA;Lin,Jia-Ren;Muhlich,JeremyL;Mittendorf,ElizabethA;Santagata,Sandro;Guerriero,JenniferL;Sorger,PeterK
• 通讯作者: Sorger,PeterK

Author Correction: Towards community-driven metadata standards for light microscopy: tiered specifications extending the OME model.

作者更正：迈向社区驱动的光学显微镜元数据标准：扩展 OME 模型的分层规范。

• DOI: 10.1038/s41592-021-01386-y
• 发表时间: 2022
• 期刊: Nature methods
• 影响因子: 48
• 作者: Hammer,Mathias;Huisman,Maximiliaan;Rigano,Alessandro;Boehm,Ulrike;Chambers,JamesJ;Gaudreault,Nathalie;North,AlisonJ;Pimentel,JaimeA;Sudar,Damir;Bajcsy,Peter;Brown,ClaireM;Corbett,AlexanderD;Faklaris,Orestis;Lacoste,Judith