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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：
10613917
负责人：
ANDREI GOGA
金额：
$ 48.8万
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/10613917
关键词：
AKT inhibition Acceleration Adhesions Architecture Basement membrane Binding Sites Bioinformatics Biological Assay Breast Breast Cancer Cell Breast Cancer Prevention Breast Epithelial Cells Cell Adhesion Molecules Cell Lineage Cell Separation Cells Chemicals Clinical Complex Dangerousness Defect Disease Disease Marker Disease Progression Drug Targeting Duct (organ) structure Entropy Epithelial Cell Proliferation Epithelial Cells Epithelium Exclusion Experimental Models Extracellular Matrix Extracellular Matrix Proteins Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Human Image In Situ In Vitro Invaded 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 Property Publishing Risk Signal Transduction Statistical Mechanics Structure System Temperature Testing Therapeutic Tissue Engineering Tissue Model Tissues Tumor Cell Invasion Western Blotting Woman breast cancer progression cell motility cell type cellular engineering derepression drug development in vivo infiltrating duct carcinoma inhibitor innovation interfacial lens malignant breast neoplasm mammary epithelium mathematical model mechanical drive mechanical energy mouse model neoplastic cell 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.

摘要