Regulation of hematopoiesis during tumor progression

项目总结/摘要 免疫系统在肿瘤进展过程中起着重要作用，具有识别和杀死肿瘤的能力。 肿瘤细胞（T细胞和NK细胞）[1]。不幸的是，这些免疫反应可以通过各种途径绕过。 机制，包括创造一个免疫抑制环境，改变T细胞和NK细胞的能力， 抑制肿瘤生长[2]。抑制抗肿瘤免疫反应的主要参与者是不成熟的 起源于骨髓的髓样细胞群。有几条证据表明， 骨髓、循环和肿瘤部位的未成熟髓细胞群数量增加，伴有疾病 恶化和生存率降低[3，4]。骨髓造血功能改变， 在癌症患者中确实观察到骨髓生成，而不管肿瘤类型和/或向骨的扩散。 然而，原发性肿瘤对骨髓造血干细胞（HSC）的影响及其相关因素 在改变它们的频率和/或功能方面仍然有待阐明。 Dkk 1是一种Wnt/β-catenin抑制剂，通过支持免疫抑制作用，在各种癌症类型中发挥免疫抑制作用。 骨髓抑制细胞群或抑制抗肿瘤免疫应答[5-7]。然而， Dkk 1在肿瘤进展过程中诱导免疫群体的变化尚未完全了解， Dkk 1对成熟免疫细胞直接作用的证据很少。有趣的是，Dkk 1是必需的 造血干细胞（HSC）再生[8]，并且过度表达可促进HSC的长期耗竭， 移植模型[9]。目前，Dkk 1在造血干细胞和祖细胞（HSPCs）中的作用 在癌症发展过程中的作用尚未研究。我的初步研究显示Dkk 1依赖性增加 原位注射EO 771乳腺癌细胞后的HSPC频率，证明了全身效应 对骨髓造血的影响 基于这些观察，这个培训机会将使我能够检验骨源性Dkk 1 改变HSPC的频率和功能，以增加骨髓生成并改变免疫景观， 肿瘤进展。因此，我提出了以下目标：目标1：揭示乳腺癌发生过程中HSPCs的变化， 目的2：研究骨源性Dkk 1在HSPC中的作用。 这些目标将揭示肿瘤进展对造血的影响以及骨在协调造血中的作用。 一个有利于肿瘤的免疫抑制环境通过这项计划接受的培训将使我 追求我对骨生物学和血液学的兴趣，加强我的研究技能，并允许我发展 在骨生物学，血液学和免疫学的交叉学术生涯所需的技能。

Project Summary/Abstract The immune system plays an important role during tumor progression, having the ability to recognize and kill tumor cells (T cells and NK cells) [1]. Unfortunately, these immune responses can be bypassed through a variety of mechanisms, including creating an immune suppressive environment that alters the ability of T cells and NK cells to inhibit tumor growth [2]. Major players in suppressing anti-tumor immune responses are immature myeloid populations originating in the bone marrow. Several lines of evidence indicate a correlation between increased numbers of immature myeloid populations in bone marrow, circulation and at tumor site, with disease progression and reduced survival [3, 4]. Altered bone marrow hematopoiesis, with skewing towards myelopoiesis, is indeed observed in cancer patients, regardless of the tumor type and/or dissemination to bone. However, the impact of a primary tumor on bone marrow hematopoietic stem cells (HSC) and the factors involved in changing their frequency and/or functionality remain to be elucidated. Dkk1, a Wnt/β-catenin inhibitor, exerts immune suppressive effects in various cancer types, by either supporting myeloid suppressor populations or inhibiting anti-tumor immune responses [5-7]. However, the mechanisms by which Dkk1 induces the changes in immune populations during tumor progression are not fully understood and evidence of direct effects of Dkk1 on mature immune cells are sparse. Interestingly, Dkk1 is required for hematopoietic stem cell (HSC) regeneration [8], and over expression can promote long-term HSC exhaustion in transplantation models [9]. Currently, the role of Dkk1 on hematopoietic stem and progenitor cells (HSPCs) during cancer progression has not been investigated. My preliminary studies show Dkk1-dependent increases in HSPC frequencies following orthotopic injection of EO771 breast cancer cells, demonstrating systemic effects of a primary tumor on bone marrow hematopoiesis. Based on these observations, this training opportunity will allow me to test the hypothesis that bone derived Dkk1 alters HSPCs frequency and function to increase myelopoiesis and transform the immune landscape during tumor progression. Thus, I propose the following aims: Aim 1: To uncover alterations to HSPCs during breast cancer progression; and Aim 2: To investigate the role of bone derived Dkk1 on HSPCs. These aims will reveal the impact of tumor progression on hematopoiesis and the role of the bone in orchestrating a tumor-conducive, immune suppressive environment. The training received through this proposal will allow me to pursue my interests in bone biology and hematology, strengthen my research skills, and allow me to develop the skill set necessary for an Academic career at the intersection of bone biology, hematology, and immunology.