Matrix density promotes pro-tumorigenic hormone actions in breast cancer

基质密度促进乳腺癌中促肿瘤激素的作用

基本信息

批准号：
10659147
负责人：
Suzanne Marie Ponik
金额：
$ 47.34万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659147
关键词：
Address Adjuvant Adjuvant Therapy Aftercare Aggressive behavior Antiestrogen Therapy Architecture Automobile Driving Biology Biopsy Breast Cancer therapy Cells Cessation of life Clinical Collagen Collagen Fiber Complement Complex Diagnosis Disease Distant Environment Equilibrium Estrogen Receptor alpha Estrogen Receptors Estrogen Therapy Estrogen receptor positive Estrogens Exhibits Experimental Models Exposure to Extracellular Matrix Fibroblasts Goals Grant Growth Hormonal Hormones Immune Immune system Immunocompetent In Vitro Inflammation Inflammation Mediators Inflammatory Intervention Invaded Knowledge Lesion Localized Disease Lung Macrophage Malignant Neoplasms Mediating Mediator Modeling Neoplasm Metastasis Operative Surgical Procedures PTGS2 gene Patients Population Primary Neoplasm Process Prognosis Recurrence Recurrent Malignant Neoplasm Residual state Role Sampling Signal Transduction Site Structure System Tamoxifen Testing Therapeutic Tissues Tumor Cell Invasion Tumor Cell Migration Tumor Promotion Woman antagonist cancer cell cancer recurrence cell growth cell motility conditioning cytokine density hormonal signals hormone therapy immunoregulation in vitro Model in vivo in vivo Model infiltrating duct carcinoma inflammatory marker lung lesion lung metastatic malignant breast neoplasm mortality mouse model neoplastic cell novel strategies patient derived xenograft model receptor response standard of care synergism therapy resistant trafficking treatment response tumor tumor microenvironment tumor progression tumor-immune system interactions tumorigenic

项目摘要

ABSTRACT Although many women with estrogen receptor positive (ER+) primary cancers are successfully treated with surgery and adjuvant anti-estrogen therapies, metastatic therapy-resistant ER+ cancers account for the majority of breast cancer related deaths. New understanding of the biology underlying disease processes is required to develop new approaches. In this renewal application, we build on our previous findings demonstrating dynamic reciprocity between estrogen and features of the extracellular matrix (ECM) in the microenvironments of both the primary tumor and the metastatic niche which fuel the pulmonary metastatic burden. We showed that estrogen remodels the ECM architecture of the primary tumor, aligning collagen fibers and increasing synthesis of ECM components associated with more aggressive cancers, and alters ECM components in the lung metastatic niche. Moreover, we showed that this collagen alignment signature in patient tumors correlates with inflammatory markers, including COX-2 and CD163+ macrophages, and poor prognosis. In the current proposal, we hypothesize that estrogen orchestrates synergy among ER+ tumor cells, the extracellular matrix (ECM)/ cancer associated fibroblasts (CAFs), and macrophages/ inflammation, to fuel primary and metastatic tumor aggression. We will utilize our robust immunocompetent in vivo model of metastatic ER+ breast cancer, in vitro systems, PDX models and clinical patient samples to test this hypothesis in the following aims. Aim 1: Identify the steps in metastatic progression of ER+ breast cancer which are altered by estrogen activity in tumor cells as well as other estrogen targets. Aim 2: Determine how estrogen action on CAFs modifies the stromal ECM to mediate tumor progression, determine the receptors that mediate this action, and identify ECM signatures from native stromal matrix from ER+ invasive ductal carcinoma biopsies that instruct estrogen action on tumor cell growth and migration. Aim 3: Determine how estrogen impacts immune metastatic mediators, including macrophage activity and the inflammatory tumor microenvironment. Aim 4: Evaluate the ability of standard of care therapeutic approaches to reverse E2-promoted steps in metastasis and post- treatment estrogen re-exposure to promote growth of residual pulmonary lesions, and interrogate the interrelationships among E2-altered ECM structure, and macrophage activity/inflammation. Our studies will illuminate the role of estrogen in dissemination and pulmonary metastatic colonization, with implications for therapy, metastatic dormancy and recurrence of ER+ breast cancer, and reveal potential sites for intervention.

抽象的尽管许多患有雌激素受体阳性（ER+）原发性癌症的女性成功通过手术和辅助抗雌激素疗法治疗转移治疗的ER+ 癌症解释了大多数与乳腺癌相关的死亡。对开发新方法需要生物学基础疾病过程。在此续约中应用程序，我们以先前的发现为基础，证明雌激素和细胞外基质（ECM）的特征原发性肿瘤和转移性生态位为肺部转移负担加油。我们展示了雌激素重塑了原发性肿瘤的ECM结构，使胶原蛋白纤维和增加与更具侵略性癌症相关的ECM成分的合成，并改变肺转移性小众中的ECM成分。此外，我们证明了这种胶原蛋白对齐患者肿瘤中的签名与炎症标记相关，包括COX-2和CD163+ 巨噬细胞和预后不良。在当前的建议中，我们假设雌激素在ER+肿瘤细胞之间协同策划，细胞外基质（ECM）/癌症相关成纤维细胞（CAF）以及巨噬细胞/炎症，以燃烧原发性和转移性肿瘤侵略。我们将在转移性ER+乳房的体内模型中使用强大的免疫能力癌症，体外系统，PDX模型和临床患者样品，以检验该假设以下目标。目标1：确定ER+乳腺癌转移性进展的步骤肿瘤细胞中的雌激素活性以及其他雌激素靶标会改变。目标2：确定雌激素对CAF的作用如何改变基质ECM以介导肿瘤进展，确定介导该动作的受体并识别来自天然基质基质的ECM特征从ER+浸润性导管癌活检，指导雌激素对肿瘤细胞生长的作用和迁移。目标3：确定雌激素如何影响免疫转移性介体，包括巨噬细胞活性和炎症性肿瘤微环境。目标4：评估逆转E2促进步骤转移和后的护理治疗方法治疗雌激素再暴露以促进残留肺部病变的生长并询问 E2改变的ECM结构以及巨噬细胞活性/炎症之间的相互关系。我们的研究将阐明雌激素在传播和肺转移中的作用殖民化，对ER+乳腺的治疗，转移性休眠和复发有影响癌症，并揭示潜在的干预部位。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rho family GTPases: making it to the third dimension.

DOI：
10.1016/j.biocel.2014.11.007
发表时间：
2015-02
期刊：
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
影响因子：
4
作者：
Riching, Kristin M.;Keely, Patricia J.
通讯作者：
Keely, Patricia J.

COX-2 modulates mammary tumor progression in response to collagen density.

DOI：
10.1186/s13058-016-0695-3
发表时间：
2016-03-22
期刊：
Breast cancer research : BCR
影响因子：
0
作者：
Esbona K;Inman D;Saha S;Jeffery J;Schedin P;Wilke L;Keely P
通讯作者：
Keely P

Prolactin Alters the Mammary Epithelial Hierarchy, Increasing Progenitors and Facilitating Ovarian Steroid Action.

DOI：
10.1016/j.stemcr.2017.08.011
发表时间：
2017-10-10
期刊：
Stem cell reports
影响因子：
5.9
作者：
O'Leary KA;Shea MP;Salituro S;Blohm CE;Schuler LA
通讯作者：
Schuler LA

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells.

I 型胶原蛋白升高会增强催乳素诱导的雌激素受体 α 阳性乳腺肿瘤细胞的肿瘤进展信号、内渗和转移。

DOI：
10.1186/s13058-017-0801-1
发表时间：
2017-01-19
期刊：
Breast cancer research : BCR
影响因子：
0
作者：
Barcus CE;O'Leary KA;Brockman JL;Rugowski DE;Liu Y;Garcia N;Yu M;Keely PJ;Eliceiri KW;Schuler LA
通讯作者：
Schuler LA

A Label-Free Segmentation Approach for Intravital Imaging of Mammary Tumor Microenvironment.

DOI：
10.3791/63413
发表时间：
2022-05-24
期刊：
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
影响因子：
1.2
作者：
Burkel, Brian M.;Inman, David R.;Virumbrales-Munoz, Maria;Hoffmann, Erica J.;Ponik, Suzanne M.
通讯作者：
Ponik, Suzanne M.