Understanding breast cancer progression as a defect in the mechanics of tissue self-organization

将乳腺癌进展理解为组织自组织机制的缺陷

基本信息

批准号：
10395995
负责人：
ANDREI GOGA
金额：
$ 56.62万
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：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10395995
关键词：
AKT inhibition Adhesions Architecture Basement membrane Binding Sites Bioinformatics Biological Assay Breast Breast Cancer Cell Breast Cancer Prevention Breast Epithelial Cells Cell Adhesion Molecules Cell Lineage Cells Chemicals Clinical Complex Dangerousness Defect Disease Disease Marker Disease Progression Drug Targeting Duct (organ) structure Entropy Epithelial Epithelial Cells Extracellular Matrix Extracellular Matrix Proteins Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Human Image In Situ In Vitro Invaded Lead Lobule Malignant Neoplasms Mammaplasty Mammary Gland Parenchyma Mammary gland Mass Spectrum Analysis Measurement Measures Mechanics Mediating Molecular Mutation Myoepithelial Noninfiltrating Intraductal Carcinoma Operative Surgical Procedures Organoids PIK3CA gene Pathway interactions Patients Penetration Peptide Hydrolases Phenotype Polycomb Positioning Attribute Probability Proliferating Property Publishing Risk Signal Transduction Statistical Mechanics Structure System Temperature Testing Therapeutic Time Tissue Engineering Tissue Model Tissues Western Blotting Woman breast cancer progression cell motility cell type cellular engineering drug development experimental study in vivo infiltrating duct carcinoma inhibitor innovation interfacial lens malignant breast neoplasm mammary epithelium mathematical model mechanical energy mouse model neoplastic cell overtreatment predictive modeling prevent programs reconstitution self organization single-cell RNA sequencing small hairpin RNA three dimensional cell culture tumor tumor progression

项目摘要

ABSTRACT A progressive breakdown in the bilayered structure of the mammary gland is the hallmark of all breast cancers, but the structural change that occurs between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) is of particular importance because it represents a major inflection point in risk for patients. Breast cancers originate in the inner luminal layer of the mammary epithelium, where transformed luminal epithelial cells (LEP) proliferate to fill the ducts and lobules in DCIS. Surprisingly, LEP in DCIS have acquired all the necessary genetic aberrations to invade, but remain constrained within the tissue by an intact outer myoepithelial (MEP) layer—a group of cells that forms a dynamic barrier blocking access of the in situ tumor to the basement membrane (BM, the specialized extracellular matrix (ECM) that surrounds the mammary epithelium). Thus, we propose that translocation of transformed LEP past the MEP layer, and not genetic mutations, is a key rate- limiting step in progression to IDC. Here, we aim to identify the physical and molecular changes that must occur in LEP to facilitate this structural transition. We approach this challenge through the lens of mammary epithelial self-organization. We previously demonstrated that normal human LEP and MEP can self-organize in vitro, and that the capacity of MEP to exclude LEP from the BM is determined by hard-wired and lineage-specific interfacial tensions at each cell-cell and cell-ECM interface. We showed using experiments and mathematical modeling that the LEP-ECM interface is highly unfavorable energetically compared to the MEP-ECM interface, which prevents LEP from positioning themselves next to the BM. We hypothesize the existence of a rate-limiting and high-energy structural intermediate during the progression of DCIS to IDC, where LEP translocate into the MEP layer, next to the BM. We propose a statistical mechanical framework for understanding how perturbations to the interfacial properties and dynamics of tumor cells facilitate the formation of this intermediate. Specifically, we predict that changes to the LEP-ECM interfacial energy are a critical physical change necessary to promote basal translocation of transformed LEP. Preliminary studies support this hypothesis: we found that a frequently dysregulated gene—PIK3CA—disrupts self-organization when activated in LEP by rendering the LEP-ECM interface more energetically favorable. In this proposal, we will determine whether this and other physical changes to LEP are necessary for their basal translocation, and identify the molecular changes downstream of PIK3CA that give rise to these physical changes. We will test our hypothesis using complementary in vitro and in vivo experimental systems: using organoids reconstituted from human reduction mammoplasty tissues and genetically engineered mouse models. Our long-term goal is to reveal the changes that promote and inhibit progression from DCIS to IDC. Better physical and molecular predictors of progression would benefit DCIS patients who would otherwise be over-treated, as only a third of DCIS cases progress to IDC. Further, blocking LEP translocation would represent a therapeutic strategy to prevent breast cancer progression.

抽象的乳腺的双层结构的逐渐崩溃是所有乳腺癌的标志，但是，导管癌（DCIS）和浸润性导管癌之间发生的结构变化（IDC）特别重要，因为它代表了患者风险的主要影响点。乳腺癌起源于乳腺上皮的内部腔内层，其中转化的腔上皮细胞（LEP）扩散以填充DCIS中的管道和小叶。令人惊讶的是，DCI中的LEP已获得了所有必要的遗传畸变要入侵，但通过完整的外肌上皮（MEP）仍在组织中限制层 - 一组单元，形成了动态屏障阻断原位肿瘤对地下室的访问膜（BM，围绕乳腺上皮的专门细胞外基质（ECM））。提议将转化的LEP易位经过MEP层而不是遗传突变是一个关键率 - 限制进步到IDC的步骤。在这里，我们旨在确定必须发生的身体和分子变化在LEP中促进这种结构过渡。我们通过乳腺上皮的镜头应对这一挑战自组织。我们以前证明了正常的人LEP和MEP可以在体外自组织，并且 MEP将LEP排除在BM之外的能力由硬线和谱系特异性界面确定每个细胞细胞和细胞ECM接口处的紧张局势。我们展示了使用实验和数学建模与MEP-ECM接口相比，LEP-ECM接口高度不利防止LEP将自己定位在BM旁边。我们假设存在限制率的存在在DCI到IDC的进展过程中，高能结构中间体，LEP转移到MEP中层，在BM旁边。我们提出了一个统计机械框架，以了解如何扰动肿瘤细胞的界面特性和动力学促进了该中间体的形成。具体来说，我们预测对LEP-ECM界面能量的变化是促进的重要物理变化转化的LEP的基本易位。初步研究支持这一假设：我们发现通过呈现LEP-ECM激活LEP，在LEP中激活时，基因失调 - PIK3CA - 散发自组织接口更有效地有利。在此提案中，我们将确定是否和其他物理 LEP的变化对于它们的基本易位是必需的，并确定下游的分子变化 PIK3CA引起了这些身体变化。我们将使用体外完整性测试我们的假设体内实验系统：使用人类还原乳腺成形术组织和基因工程的鼠标模型。我们的长期目标是揭示促进和抑制的变化从DCI到IDC的发展。更好的身体和分子预测指标将使DCIS受益否则会过度治疗的患者，因为只有三分之一的DCIS病例发展为IDC。此外，阻止 LEP易位将代表一种预防乳腺癌进展的治疗策略。