Myc promoted changes to the glycocalyx in leukemia

项目总结 转录因子c-myc(Myc)在大多数人类恶性肿瘤中过表达，并与 具有侵袭性的癌症表型和糟糕的患者预后。最近，MYC被牵连到促进 白血病通过上调抑制免疫细胞的检查点蛋白来逃避免疫系统 功能。然而，我们对MYC如何塑造肿瘤微环境的了解是不完整的。 癌细胞的糖基化可能是部分答案。特异性fi，肿瘤细胞低聚糖含有 已知唾液酸(唾液酸苷)与白细胞(如自然杀伤细胞)上的Siglec受体结合 和巨噬细胞。Siglecs是一个受体家族，与检查点蛋白PD-1和CD47一样， 含有能够阻止免疫激活的信号域。因此，唾液酸苷的展示是一种 肿瘤逃避免疫系统的策略。作为一种转录因子和细胞外信号调节因子 新陈代谢，MYC可能是癌症产生调节免疫的唾液酸苷的罪魁祸首 系统。我发现MYC直接调节唾液酸转移酶，这种酶将唾液酸添加到 低聚糖。这项建议建立在这些fi编码的基础上，目标是表征唾液酸苷 抑制MYC驱动的白血病模型的免疫系统。使用遗传和化学工具，我将 阐明MYC促进肿瘤中唾液酸苷合成的机制(目标1)。然后我会研究这些 唾液酸苷利用白血病体内模型确定MYC对糖基化的调节作用 巨噬细胞的功能，以及一般的肿瘤微环境(目标2)。机械师 MYC驱动白血病中唾液酸苷的合成及其下游免疫调节的认识 功能，将促进针对唾液酸和糖基化的新型免疫疗法的开发。 在此提出的项目将为我提供大量的学术和专业发展机会 技能，因为我继续我的培训，成为一名临床医生研究员。我介绍的工作将在斯坦福大学进行 在卡罗琳·贝尔托齐的实验室里，她是一位杰出的化学家和糖生物学家，她将在我 成为一名独立调查员。我还会得到肿瘤学家和肿瘤免疫学家的进一步建议 Felsher博士和Ravi Majeti博士。斯坦福大学的资源和环境非常适合 支持我成为一名拥有自己实验室的血液学家和肿瘤学家。

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.