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Three-dimensional organoid models to study breast cancer progression

研究乳腺癌进展的三维类器官模型

基本信息

批准号：
10581806
负责人：
Shilpa Sant
金额：
$ 42.3万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581806
关键词：
3-Dimensional AKT Signaling Pathway Address Agreement Antitumor Response Award Biomedical Engineering Breast Cancer Detection Breast Cancer Patient CCL2 gene CXCL10 gene CXCR3 gene Cancer cell line Carcinoma in Situ Cause of Death Cell Line Cell secretion Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Coupled Development Diagnosis Drug Screening Duct (organ) structure E-Cadherin Engineering Environment Epidermal Growth Factor Receptor Exhibits Experimental Models Fibronectins Genetic Heterogeneity Hybrids Hypoxia IL7 gene IL8 gene Image Analysis In Vitro Individual Interleukin-10 Interleukin-15 Interleukin-6 Invaded Knock-in Knowledge Label Lead Left Link Maintenance Malignant - descriptor Malignant Neoplasms Mammography Matrix Metalloproteinases Metabolic stress Metastatic breast cancer Micro Array Data Microarray Analysis Modeling Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Organoids Outcome PI3K/AKT PIK3CG gene Parents Pathway interactions Patients Peripheral Phenotype Pleural Pleural effusion disorder Prognostic Marker Proteins Reproducibility Resolution Role Sampling Signal Pathway Signal Transduction Site Sorting Spatial Distribution Stimulus Stress Structure System Testing Therapeutic Time Variant Vimentin Visualization Woman Work breast cancer progression clinically relevant confocal imaging cytokine deep learning deep learning algorithm design effective therapy gene regulatory network genetic signature genomic profiles imaging approach improved in vitro Model in vivo infiltrating duct carcinoma innovation malignant breast neoplasm meter migration neoplastic cell new therapeutic target novel overtreatment paracrine premalignant prevent progression risk rho GTP-Binding Proteins risk prediction therapy development treatment strategy tumor tumor heterogeneity

项目摘要

Abstract Approximately 20% of breast cancers detected through mammography are pre-invasive Ductal Carcinoma in situ (DCIS). If left untreated, approximately 20-50% of DCIS will progress to more deadly Invasive Ductal Carcinoma (IDC). No prognostic biomarkers can reliably predict the risk of progression from DCIS to IDC. Similar genomic profiles of matched pre-invasive DCIS and IDC suggests that the progression is not driven by genetic aberrations in DCIS cells, but microenvironmental factors, such as hypoxia and metabolic stress prevalent in DCIS, may drive the transition. We need innovative models to investigate how to halt steps of DCIS progression to invasive phenotypes and subsequent metastasis from the primary site. This proposal directly addresses this unmet need by developing a novel three-dimensional in vitro organoid model that recapitulates key hallmarks of DCIS to IDC progression: tumor-size induced hypoxia and metabolic stress, tumor heterogeneity and spontaneous emergence of migratory phenotype in the same parent cells without any additional stimulus. A tangible advantage of the proposed organoid models is the ability to precisely and reproducibly study how the hypoxic microenvironment induces tumor migration in real time and in isolation from non-tumor cells present in vivo, providing unique opportunity to define tumor-intrinsic mechanisms of DCIS to IDC progression. During July 2018-Feb 2022 ESI MERIT Award period, we have shown that inhibition of tumor-secreted factors effectively halts organoid migration, while inhibition of hypoxia is effective only within a time window and is compromised by tumor-to-tumor variation, supporting our notion that hypoxia initiates migratory phenotypes but does not sustain it. We have also analyzed secretome from metastatic breast cancer pleural effusion showing significantly higher levels of CCL2/MCP1, CXCL10/IP10, IL-6, IL-8, regulatory IL-10, and IL-7 and IL-15. Strategies to neutralize these key cytokines may generate anti-tumor responses in the pleural environment. Microarray analysis of hypoxia-induced migration and secretome-induced migration suggested role of Rho GTPase and PI3K/AKT signaling pathways in maintaining migration. Our results show that hypoxic organoid models exhibit partial EMT signatures as early as day 1, which is maintained as these non-migratory organoids transition to migratory phenotypes. During the two-year extension period, we will continue 1) to optimize our DCIS models incorporating ductal structure and other components from DCIS microenvironments; 2) to test new mechanisms linking tumor-intrinsic hypoxia, partial/hybrid EMT and collective migration; 3) to inhibit signaling mechanisms to halt emergence of migratory phenotypes. The successful completion of the proposed work will provide answers to two fundamental questions in the progression of invasive breast cancer: 1) What causes some DCIS cells to become migratory and develop into invasive tumors? 2) How and where does the migratory phenotype (IDC) emerge? The mechanistic understanding gained from these studies will improve diagnosis, lead to the development of treatment strategies to arrest invasion at the pre-malignant stage, and thus prevent patient overtreatment.

摘要通过乳房X线摄影检测到的乳腺癌中约有20%是浸润前导管癌，原位（DCIS）。如果不及时治疗，大约20-50%的DCIS会发展为更致命的浸润性导管癌。癌（IDC）。没有预后生物标志物可以可靠地预测从DCIS进展到IDC的风险。类似匹配的浸润前DCIS和IDC的基因组图谱表明，进展不是由遗传驱动的， DCIS细胞中的畸变，但微环境因素，如缺氧和代谢应激普遍存在， DCIS可能会推动转型。我们需要创新的模型来研究如何阻止DCIS进展的步骤侵袭性表型和随后的原发部位转移。该提案直接针对通过开发一种新的三维体外类器官模型， DCIS进展为IDC的标志：肿瘤大小诱导的缺氧和代谢应激，肿瘤异质性以及在没有任何额外刺激的情况下在相同亲本细胞中自发出现迁移表型。一所提出的类器官模型的明显优势是能够精确和可重复地研究细胞如何在体内生长。缺氧微环境诱导肿瘤在真实的时间内迁移，并与存在于体内，提供了独特的机会来定义DCIS到IDC进展的肿瘤内在机制。在2018年7月至2022年2月的ESI MERIT奖期间，我们已经证明抑制肿瘤分泌因子有效地阻止类器官迁移，而缺氧的抑制仅在一个时间窗内有效，并且肿瘤间变异的影响，支持我们的观点，即缺氧启动迁移表型，我们还分析了转移性乳腺癌胸腔积液的分泌蛋白组，显著更高水平的CCL 2/MCP 1、CXCL 10/IP 10、IL-6、IL-8、调节性IL-10以及IL-7和IL-15。中和这些关键细胞因子的策略可以在胸膜环境中产生抗肿瘤反应。缺氧诱导的迁移和分泌组诱导的迁移的微阵列分析表明Rho的作用 GT3和PI 3 K/AKT信号通路在维持迁移中的作用。我们的研究结果表明，缺氧类器官模型早在第1天就表现出部分EMT特征，这是因为这些非迁移性类器官向迁移表型过渡。在两年的延长期内，我们将继续1）优化我们的DCIS模型， DCIS微环境中的结构和其他成分; 2）测试将肿瘤内在缺氧、部分/混合EMT和集体迁移; 3）抑制信号传导机制以阻止迁移表型拟议工作的圆满完成将为《公约》中的两个基本问题提供答案。浸润性乳腺癌的进展：1）是什么原因导致一些DCIS细胞迁移并发展成侵袭性肿瘤2)迁移表型（IDC）是如何以及在何处出现的？机械论从这些研究中获得的理解将改善诊断，导致治疗策略的发展，以在癌前阶段阻止侵袭，从而防止患者过度治疗。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identifying Molecular Signatures of Distinct Modes of Collective Migration in Response to the Microenvironment Using Three-Dimensional Breast Cancer Models.

DOI：
10.3390/cancers13061429
发表时间：
2021-03-20
期刊：
Cancers
影响因子：
5.2
作者：
Ardila DC;Aggarwal V;Singh M;Chattopadhyay A;Chaparala S;Sant S
通讯作者：
Sant S

P4HA2: A link between tumor-intrinsic hypoxia, partial EMT and collective migration.

P4HA2：肿瘤内在缺氧、部分 EMT 和集体迁移之间的联系。

DOI：
10.1016/j.adcanc.2022.100057
发表时间：
2022
期刊：
Advances in cancer biology - metastasis
影响因子：
0
作者：
Aggarwal,Vaishali;Sahoo,Sarthak;Donnenberg,VeraS;Chakraborty,Priyanka;Jolly,MohitKumar;Sant,Shilpa
通讯作者：
Sant,Shilpa

Mathematical Modeling of Plasticity and Heterogeneity in EMT.