Myc promoted changes to the glycocalyx in leukemia

Myc 促进白血病糖萼的变化

• 批准号: 10221644
• 负责人: Benjamin Arthur Humphers Smith
• 金额: $ 2.95万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2021-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221644
• 关键词: Affect; Anabolism; Binding; CD47 gene; Cell Line; Cell Proliferation; Cell physiology; Cell surface; Characteristics; Chemicals; Data Set; Dependence; Development; Doctor of Philosophy; Environment; Enzymes; Family; Flow Cytometry; Fostering; Gene Expression; Genetic; Glycobiology; Glycocalyx; Goals; Hematologist; Human; ITIM; Immune; Immune Evasion; Immune system; Immunologist; Immunotherapy; Innate Immune System; Laboratories; Leukocytes; Ligands; MYC gene; Malignant Neoplasms; Measures; Mentors; Metabolism; Mining; Modeling; Mus; Natural Killer Cells; Oligosaccharides; Oncogenes; Oncogenic; Oncologist; Patient-Focused Outcomes; Pattern; Phenotype; Polysaccharides; Process; Production; Proteins; Publishing; Research Personnel; Resources; Role; Sampling; Shapes; Sialic Acids; Sialyltransferases; Signal Transduction; Supervision; Therapeutic; Training; Tumor-infiltrating immune cells; Universities; Work; c-myc Genes; cancer cell; glycosylation; immune activation; immune clearance; immune function; immunoregulation; immunosuppressed; in vivo; in vivo Model; inhibitor/antagonist; leukemia; macrophage; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; prevent; programmed cell death ligand 1; programmed cell death protein 1; receptor; sialic acid binding Ig-like lectin; skills; small molecule; tool; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumorigenesis

PROJECT SUMMARY The transcription factor c-MYC (MYC) is overexpressed in a majority of human malignancies and is associated with aggressive cancer phenotypes and poor patient outcomes. Recently, MYC was implicated in promoting leukemia's evasion of the immune system by up-regulating checkpoint proteins that suppress immune cell function. However, our understanding of how MYC shapes the tumor microenvironment is incomplete. Glycosylation of cancer cells could be part of the answer. Specifically, tumor cell oligosaccharides containing sialic acid (sialosides) are known to engage Siglec receptors on white blood cells such as natural killer cells and macrophages. The Siglecs are a family of receptors that, like the checkpoint proteins PD-1 and CD47, contain signaling domains capable of preventing immune activation. Therefore, display of sialosides is a strategy employed by tumors to evade the immune system. As a transcription factor and regulator of cellular metabolism, MYC is a likely culprit behind cancer's presentation of sialosides that regulate the immune system. I found that MYC directly regulates the sialyltransferases, the enzymes that append sialic acid to oligosaccharides. This proposal builds off these findings with the goal of characterizing sialosides capable of inhibiting the immune system in models of MYC driven leukemia. Using genetic and chemical tools, I will delineate the mechanism of sialoside synthesis promoted by MYC in cancer (Aim 1). I will then study these sialosides using in vivo models of leukemia to determine how MYC's modulation of glycosylation affects macrophage function in particular, and the tumor microenvironment in general (Aim 2). A mechanistic understanding of sialoside synthesis in MYC driven leukemias, and the downstream modulation of immune function, will promote the development of novel immunotherapies targeting sialic acid and glycosylation. The project presented herein will provide me with ample opportunities to develop academic and professional skills as I continue my training to become a clinician investigator. The work I present will take place at Stanford University in the lab of Carolyn Bertozzi, a prominent chemist and glycobiologist, who will mentor me as I become an independent investigator. I will be further advised by oncologists and tumor immunologists Dean Felsher, MD PhD; and Ravi Majeti, MD PhD. The resources and environment at Stanford are ideal for supporting me toward becoming a hematologist-oncologist with my own laboratory.

项目摘要 转录因子C-MYC（MYC）在大多数人类恶性肿瘤中都过表达，并且相关 具有侵略性的癌症表型和差的患者结局。最近，MYC暗示着促进 白血病通过上调抑制免疫球的检查点蛋白来对免疫系统的进化 功能。但是，我们对MYC如何塑造肿瘤微环境的理解是不完整的。 癌细胞的糖基化可能是答案的一部分。含有特定的肿瘤细胞寡糖 已知唾液酸（唾液酸）在白细胞（如天然杀伤细胞）上吸收Siglec受体 和巨噬细胞。 Siglecs是一个受体家族，例如检查点蛋白PD-1和CD47， 包含能够防止免疫激活的信号域。因此，显示唾液苷是 肿瘤采用的策略逃避免疫系统。作为细胞的转录因子和调节剂 代谢，MYC可能是癌症呈现调节免疫的唾液酸的罪魁祸首的罪魁祸首 系统。我发现MYC直接调节了辅助转移酶，该酶是将唾液酸添加到的酶 寡糖。该提议建立在这些发现的基础上，目的是表征能够 抑制MYC驱动白血病模型中的免疫系统。使用遗传和化学工具，我将 描述了MYC在癌症中促进的唾液洛糖苷合成的机理（AIM 1）。然后我将研究这些 使用白血病的体内模型来确定MYC的糖基化调节如何影响 巨噬细胞的功能尤其是肿瘤微环境（AIM 2）。机械 了解MYC驱动白血病中的唾液酸合成和免疫的下游调节 功能将促进针对唾液酸和糖基化的新型免疫疗法的发展。 本文提出的项目将为我提供足够的机会来发展学术和专业 当我继续培训成为临床研究者时，技能。我提出的工作将在斯坦福举行 杰出的化学家和糖生物学家Carolyn Bertozzi实验室的大学 成为独立研究者。肿瘤学家和肿瘤免疫学家院长将进一步建议我 Felsher，医学博士；和Ravi Majeti，医学博士。斯坦福的资源和环境是理想的选择 支持我通过自己的实验室成为血液学医生。