Project 2: NITRIC OXIDE IN THE TUMOR MICROENVIRONMENT OF TRIPLE NEGATIVE BREAST CANCER

项目2：三阴性乳腺癌肿瘤微环境中的一氧化氮

基本信息

批准号：
10251191
负责人：
Narendiran Rajasekaran
金额：
$ 18.81万
依托单位：
NORTHERN ARIZONA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251191
关键词：
4T1 Address Affect Aggressive behavior Allografting Arizona Breast Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast Cancer therapy Budgets CD47 gene CRISPR/Cas technology Cancer Biology Cancer Center Cells Clinical Research Collaborations Communities Cytotoxic T-Lymphocytes Data Disseminated Malignant Neoplasm Education and Outreach Ensure Epidermal Growth Factor Receptor Ethnic Origin Focus Groups Funding Gene Expression Profile Genes Glycolysis Goals Grant Growth HIF1A gene Human Hypoxia Hypoxia Inducible Factor Immune Immune Evasion Immune system Immunocompetent Immunohistochemistry Immunosuppression In Vitro Investigation Laboratories Link MCF10A cells MCF7 cell MDA-MB-468 Malignant Neoplasms Membrane Proteins Metastatic breast cancer Modeling Monitor Mus Myeloid-derived suppressor cells NOS2A gene Native Americans Natural Immunity Natural Killer Cells Navajo Nitric Oxide Nitric Oxide Signaling Pathway Nonmetastatic Not Hispanic or Latino Oncology Outcome PIM1 gene Paper Patients Phenotype Phosphotransferases Population Procollagen-Proline Dioxygenase Production Proteins Publications Research Research Personnel Role Scientist Signal Transduction Solid Soluble Guanylate Cyclase Students Therapeutic Training Translational Research Tumor Cell Invasion Tumor Escape Tumor Promotion Tumor Suppressor Proteins Tumor-Derived Universities Vascularization Woman Work Xenograft procedure adaptive immune response anticancer research base cancer prevention career cell motility chemokine cytokine education research experimental study high risk immune checkpoint blockade immune clearance in vivo in vivo Model inhibitor/antagonist macrophage malignant breast neoplasm migration mouse model neoplastic cell novel therapeutic intervention novel therapeutics professor programmed cell death ligand 1 receptor recruit side effect structural biology student training targeted treatment therapeutic development transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT: PROJECT 2 NITRIC OXIDE IN THE TUMOR MICROENVIRONMENT OF TRIPLE NEGATIVE BREAST CANCER We propose to uncover how tumor produced nitric oxide drives tumor aggressiveness and immune evasion in triple negative breast cancer (TNBC). We also seek to increase research opportunities in cancer biology for Native American students. TNBC is an aggressive and metastatic form of breast cancer for which there are no targeted therapies. TNBC disproportionately affects Native American women and leads to worse outcomes than for non-Hispanic White women. Overall, Native American women have a 30-70% higher risk of dying from breast cancer when compared to other ethnicities. Our long-term goals are to develop much-needed new therapies for TNBC and to increase the pool of Native Americans with a focus on cancer research. Our team brings together Dr. Narendiran Rajasekaran, an Assistant Professor at Northern Arizona University (NAU) with a strong background in cancer biology and innate immunity, and Dr. William Montfort, a University of Arizona Cancer Center Professor with strength in structural biology, therapeutic development and nitric oxide signaling. Our project meshes with the Partnership for Native American Cancer Prevention (NACP) through our focus on a form of cancer of high importance to the Native American community, and through our efforts to train emerging Native American scientists in cancer biology. Our preliminary data uncover a link between tumor-derived nitric oxide and enhanced hypoxic signaling, which leads to a gene expression profile favoring tumor promotion, including growth, glycolysis, migration and immune cell evasion. We have three aims. Aim 1 is to uncover how nitric oxide induces tumor progression, using three breast cancer cell lines for in vitro work and the 4T1 allograft murine model for in vivo work. Aim 2 is to uncover how nitric oxide induces tumor evasion of innate immunity through checkpoint blockade involving CD47 and PD-L1, and cytokine production. Focus is on both macrophages and natural killer cells and will make use of both xenograft and allograft breast cancer models. Aim 3 is to recruit and train Native American students in cancer biology and increase the opportunities for cancer research at NAU. Native American students will be recruited into both laboratories. A particular focus will be on ensuring Prof. Rajasekaran successfully establishes his new laboratory at NAU with solid student training, funding and publications.

项目摘要/摘要：项目2 三重阴性乳腺癌肿瘤微环境中的一氧化氮我们建议揭示肿瘤如何产生一氧化氮的如何驱动肿瘤的侵袭性和免疫逃避三重阴性乳腺癌（TNBC）。我们还寻求增加癌症生物学的研究机会美国原住民学生。 TNBC是一种侵略性和转移性形式的乳腺癌，没有靶向疗法。 TNBC不成比例地影响美国原住民妇女，并导致比对于非西班牙裔白人妇女。总体而言，美洲原住民妇女因乳房死亡的风险增加了30-70％与其他种族相比，癌症。我们的长期目标是开发急需的新疗法 TNBC并增加美洲原住民的池，重点是癌症研究。我们的团队聚集在一起北亚利桑那大学（NAU）的助理教授Narendiran Rajasekaran博士，有一个强大的癌症生物学和先天免疫的背景，以及亚利桑那大学癌症的威廉·蒙特福特博士中心教授具有结构生物学，治疗性发育和一氧化氮信号的力量。我们的通过我们的专注于形式对美洲原住民社区的癌症高度重要，并通过我们努力培训新兴的本地美国癌症生物学科学家。我们的初步数据发现了肿瘤衍生的一氧化氮与增强的低氧信号之间的联系，这导致有利于肿瘤促进的基因表达谱，包括生长，糖酵解，迁移和免疫细胞逃避。我们有三个目标。目标1是使用三个乳房发现一氧化氮如何诱导肿瘤进展用于体外工作的癌细胞系和体内工作的4T1同种异体移植鼠模型。目标2是揭示如何一氧化氮通过涉及CD47和PD-L1的检查点封锁诱导肿瘤逃避先天免疫力，和细胞因子产生。重点是巨噬细胞和天然杀伤细胞，将同时使用异种移植和同种异体乳腺癌模型。目标3是招募和培训美国原住民的癌症学生生物学并增加NAU癌症研究的机会。美国原住民学生将被招募进入两个实验室。特别的重点将是确保拉贾塞卡兰教授成功建立他的新 NAU的实验室，并通过扎实的学生培训，资金和出版物。