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. Speci?cally, 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 ?ndings 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.
Cancer cells are distinguished from their healthy counterparts by altered patterns of cell surface glycosylation and elevated sialic acid levels. A longstanding question has been how oncogenes control this process, and how this might be exploited therapeutically. By working to understand how the Myc oncogene promotes display of sialic acid containing glycans, this proposal will answer fundamental questions in glycobiology and open new avenues for immunotherapies.
