SEMA6D-mediated breast cancer disparity, metastasis, and tumor-immune interaction

项目摘要 乳腺癌（BC）是女性中最常见的癌症，也是导致乳腺癌的第二大原因。 女性癌症死亡率。BC致死性主要由转移引起。非裔美国人（AA）显示 比白种美国（CA）女性更早发生BC，更有可能被诊断为转移性类型 三阴性乳腺癌（TNBC）在提出时，并有一个显着较高的死亡率。 我们的长期目标是确定BC结果中种族差异的生物学因素，并制定 新的临床应用以消除这种差异。我们的生物信息学分析显示，脑信号蛋白6D 乳腺癌组织中SEMA 6D的表达显著低于正常乳腺组织。注意， 与CA癌组织相比，AA癌组织中SEMA 6D的两种主要同种型减少。的 SEMA 6D的低表达水平与患者存活率差显著相关。我们对蛋白质的分析 表达证实SEMA 6D蛋白的表达在AA BC组织中也比在CA TNBC组织中低。 我们的功能测试表明，在BC细胞中SEMA 6D的过表达显著降低了它们在乳腺癌中的转移。 vivo.为了更好地理解SEMA 6D在BC中的作用，我们使用 自发性小鼠BC肿瘤。我们发现SEMA 6D缺陷导致转移性癌基因表达增加， 肿瘤细胞中的基因和增强的一组免疫抑制细胞在肿瘤中的积累 微环境我们假设SEMA 6D通过涉及肿瘤和淋巴结转移的机制来抑制BC转移。 内源性信号传导和肿瘤微环境，SEMA 6D的差异表达是导致肿瘤微环境改变的原因。 AA和CA患者之间观察到的结果差异的因素。在目标1中，我们将确定机制 BC样品中SEMA 6D的种族差异表达。在目标2中，我们将测试功能 SEMA 6D差异表达在调节AA和CA细胞转移中意义在目标3中，我们 阐明SEMA 6D抑制AA和CA TNBC细胞转移的机制。完成 这项研究将为理解不列颠哥伦比亚省种族差异的生物学基础提供重要线索， 开发新的诊断/治疗方法来消除这种差异。

Project Summary Breast cancer (BC) is the most commonly diagnosed cancer in women and is also the second leading cause of cancer death in women. BC lethality is primarily caused by metastasis. African American (AA) women display earlier onset of BC than Caucasian American (CA) women, are more likely to be diagnosed with metastatic types of triple-negative breast cancer (TNBC) at the time of presentation, and have a significantly higher mortality rate. Our long-term goal is to identify the biological factors underlying racial disparities in BC outcomes and to develop novel clinical applications to eliminate such disparities. Our bioinformatic analysis revealed that Semaphorin 6D (SEMA6D) expression was dramatically lower in BC tissues than normal breast tissues. Of note, expression of two prominent isoforms of SEMA6D were reduced in AA cancer tissues compared to CA cancer tissues. The low expression level of SEMA6D correlates significantly with poor patient survival. Our analysis of protein expression confirmed that expression of SEMA6D protein is also lower in AA BC tissues than in CA TNBC tissues. Our functional test showed that overexpression of SEMA6D in BC cells dramatically reduced their metastasis in vivo. To better understand the role of SEMA6D in BC, we performed single cell RNA-Sequencing analysis using spontaneous mouse BC tumors. We found that SEMA6D-deficiency led to increased expression of metastatic genes in tumor cells and enhanced accumulation of a group of immunosuppressive cells in the tumor microenvironment. We hypothesize that SEMA6D inhibits BC metastasis via mechanisms involving both tumor- intrinsic signaling and the tumor microenvironment, and that differential expression of SEMA6D is a causative factor for outcome disparities observed between AA and CA patients. In Aim 1, we will determine the mechanism underlying differential expression of SEMA6D by race in BC samples. In Aim 2, we will test the functional significance of differential expression of SEMA6D in regulating metastasis of AA and CA cells. In Aim 3, we will elucidate the mechanism by which SEMA6D suppresses metastasis of AA and CA TNBC cells. Accomplishing this study will provide crucial clues for understanding the biological basis for BC racial disparities and will facilitate development of novel diagnostic/therapeutic approaches to eliminate such disparities.