Project 2: Nitric Oxide in the Tumor Micorenviroment of Triple Negative Breast Cancer

项目摘要/摘要：项目2 三阴性乳腺癌肿瘤微环境中一氧化氮的表达 我们建议揭示肿瘤产生的一氧化氮是如何驱动肿瘤侵袭性和免疫逃避的 三阴性乳腺癌(TNBC)我们还寻求增加癌症生物学的研究机会 美洲土著学生。TNBC是一种侵袭性和转移性的乳腺癌，目前尚无治疗方法 有针对性的治疗。TNBC对美洲原住民妇女的影响不成比例，并导致比 为非西班牙裔白人女性准备的。总体而言，美洲原住民妇女死于乳房的风险要高出30%-70% 癌症与其他种族相比。我们的长期目标是开发急需的新疗法 TNBC和增加美洲原住民的人才库，重点是癌症研究。我们的团队聚集在一起 Narendiran Rajasekaran博士，北亚利桑那大学(NAU)助理教授，拥有强大的 癌症生物学和先天免疫背景，亚利桑那大学癌症威廉·蒙福特博士 中心教授，在结构生物学、治疗发展和一氧化氮信号方面有很强的实力。我们的 通过我们对表格的关注，该项目与美洲原住民癌症预防伙伴关系(NACP)相吻合 癌症对美洲原住民社区的高度重要性，并通过我们努力培训新兴的原住民 癌症生物学领域的美国科学家。 我们的初步数据揭示了肿瘤来源的一氧化氮和增强的低氧信号之间的联系，这 导致促进肿瘤的基因表达谱，包括生长、糖酵解、迁移和免疫细胞 逃避。我们有三个目标。第一个目标是揭示一氧化氮如何导致肿瘤进展，使用三个乳房 肿瘤细胞系为体外工作，4T1同种异体小鼠模型为体内工作。目标2是揭示如何 一氧化氮通过CD47和PD-L1的检查点阻断诱导肿瘤逃逸先天免疫 和细胞因子的产生。重点是巨噬细胞和自然杀伤细胞，并将利用这两种细胞 异种移植和同种异体乳腺癌模型。目标3是招募和培训美洲原住民的癌症学生 生物学和增加北大西洋公约大学癌症研究的机会。美国原住民学生将被录取 进入两个实验室。一个特别的重点将是确保Rajasekaran教授成功地建立他的新 NAU的实验室，有扎实的学生培训、资金和出版物。

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.