The role of microenvironment in aging-related phenotypes of breast

微环境在乳腺衰老相关表型中的作用

基本信息

批准号：
8278551
负责人：
Mark A LaBarge
金额：
$ 22.1万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2014-04-30
项目状态：
已结题

项目摘要

The mechanisms underlying the exponentially increased incidence of breast cancer in women >55 years of age are poorly understood. A useful conceptual framework from which to build hypotheses is that agingrelated phenotypes are etiologically rooted in changes In tissue-specific stem cells or in their regulation. Indeed, common aging-related phenotypes i.e. cancers and deficits in tissue regeneration both have been linked to stem cells. A number of reports that studied stem cells as a function of age have suggested that age-related phenotypes can be due to stem cell-intrinsic or-extrinsic factors, but that delineation appears to be tissue specific. The Bissell laboratory and others have shown that the mammary microenvironment is as important as are the mutations in epithelial tumor cells for development of breast cancers. In a number of cases it has even been shown that the microenvironment can be dominant over strong oncogenes. In the aging breast, does the microenvironment change so as to catalyze tumorigenesis? Do damaged or aged mammary stem cells cease listening to, or misinterpret regulatory cues from their microenvironment? Or is it a combination? We are now uniquely poised to address these questions for the breast. Over several decades, 3-dimensional culture models that mimic many aspects ofthe human mammary gland and breast cancer microenvironments were developed in the Bissell laboratory. Recently, we also have developed a cell-based microenvironment microarray technology that facilitates elucidation of the functional roles that are played by individual microenvironmental constituents and combinations thereof. We have used these models together with primary human mammary progenitor cells to demonstrate that the microenvironment can dictate mammary progenitor cell fate decisions. Here we propose to combine these assets to address the following specific aims: (1) To identify age-dependent functional responses in microenvironment-directed mammary progenitor cell regulation, and the genetic circuitry that underlies them. (2) To determine whether mutations characteristic of breast cancers endow normal mammary progenitor cells with tumor-forming potential, or shifts their spectrum of response to mammary microenvironments in an age-dependent manner. (3) To design and test a therapeutic strategy based on age-related differences in mammary microenvironments and stem cell behavior using physiologically relevant 3D organotypic assays.

妇女中乳腺癌的发生率指数增加的机制> 55年年龄知之甚少。建立假设的一个有用的概念框架是与年龄相关的框架表型在病因上根植于组织特异性干细胞的变化或其调节。实际上，常见的与衰老相关的表型，即癌症和组织再生的缺陷都是与干细胞有关。许多研究干细胞随着年龄的影响的报告表明与年龄相关的表型可能是由于干细胞中性或过时因素引起的，但这种描述似乎是特定于组织。 Bissell实验室和其他实验室表明，乳腺微环境如重要的是，上皮肿瘤细胞中的突变对于乳腺癌的发展也很重要。在多个案例甚至已经表明，微环境可以在强肿瘤基因上占主导地位。在乳房衰老，微环境会改变以催化肿瘤发生吗？损坏或老化乳腺干细胞停止听取或误解其微环境的调节线索？还是它组合？现在，我们有独特的准备解决这些问题的乳房。多个几十年来，模仿人类乳腺和乳腺的许多方面的三维文化模型癌症的微环境是在Bissell实验室中开发的。最近，我们也开发了基于细胞的微环境微阵列技术，促进了功能角色的阐明由单个微环境组成部分及其组合扮演。我们已经使用了这些模型与原代人乳腺祖细胞一起证明微环境可以决定乳腺祖细胞命运决定。在这里，我们建议将这些资产结合起来，以解决以下特定目的：（1）识别以微环境为导向的年龄依赖性功能响应乳腺祖细胞调节及其基础的遗传回路。（2）确定是否乳腺癌的突变特征是具有肿瘤形成潜力的正常乳腺祖细胞，或以年龄的方式改变了他们对乳腺微环境的反应范围。（3）设计和测试基于乳腺微环境和干细胞年龄相关差异的治疗策略使用生理相关的3D器官测定法行为。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High-Dimensional Phenotyping Identifies Age-Emergent Cells in Human Mammary Epithelia.

DOI：
10.1016/j.celrep.2018.03.114
发表时间：
2018-04-24
期刊：
Cell reports
影响因子：
8.8
作者：
Pelissier Vatter FA;Schapiro D;Chang H;Borowsky AD;Lee JK;Parvin B;Stampfer MR;LaBarge MA;Bodenmiller B;Lorens JB
通讯作者：
Lorens JB

Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia.

DOI：
10.1158/0008-5472.can-12-0157
发表时间：
2012-07-15
期刊：
Cancer research
影响因子：
11.2
作者：
Garbe JC;Pepin F;Pelissier FA;Sputova K;Fridriksdottir AJ;Guo DE;Villadsen R;Park M;Petersen OW;Borowsky AD;Stampfer MR;Labarge MA
通讯作者：
Labarge MA

Microsphere cytometry to interrogate microenvironment-dependent cell signaling.

微球细胞术用于询问微环境依赖性细胞信号传导。