Glycans attached to cell-surface proteins and lipids mediate interactions with receptors on other cells, the extracellular matrix (ECM), or molecules on the same cell membrane. As well, cell-surface glycoconjugates collectively form the glycocalyx, a structure with bulk physical properties that can influence extracellular interactions Cell-surface glycosylation patterns often shift in response to cellular changes, most notably during malignant transformation. Two frequently observed cancer-associated phenotypes are cell-surface mucin overexpression and hypersialylation, but the functional significance of these altered glycoprofiles is not well understood. More broadly, while much work has been devoted to characterizing cancer glycomes, there are very few examples in which tumor-associated glycoconjugates have been ascribed specific cancer-related functions. The broad objectives of this project are to (1) develop chemical approaches for engineering structurally defined glycoconjugates on cells, and (2) shed light on the functional significance of cancer-associated glycosylation motifs using these methods.
We aim to generate synthetic glycopolymers and protein/glycopolymer chimeras that emulate the structures and biological properties of cell surface mucin glycoproteins (Aim 1). We will use these materials and methods to engineer the display of chemically defined mucin mimetics on live cells, where we can probe their contribution to cancer-related processes. Specifically, we will test the emerging hypothesis that mucin overexpression alters the physical properties of the cell surface glycocalyx so as to promote integrin clustering and cell survival in non-adherent settings (Aim 2). This component of the project is a collaborative effort with Prof. Valerie Weaver's laboratory at UCSF. Finally, we will determine whether hypersialylation engineered via cell surface glycopolymer display protects cancer cells from innate immune destruction by NK cells (Aim 3). Such protection, and the selective advantage it confers, could explain the widespread occurrence of hypersialylation among disparate cancer types.
All human cells are coated with complex sugar molecules, also called glycans, whose functions are not well understood. It is known, however, that glycans change when tumor cells become metastatic, and that cell-surface sugars can affect the way our immune system reacts to cancer cells. This project seeks to develop technologies rooted in chemistry that can be used to better understand how sugars contribute to cancer and to the immune response; in the long-term, this work may help us identify new avenues for cancer therapy. !
| Barnes, J Matthew; Kaushik, Shelly; Bainer, Russell O et al. (2018) A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma. Nat Cell Biol 20:1203-1214 |
| Zhou, Matthew N; Delaveris, Corleone S; Kramer, Jessica R et al. (2018) N-Carboxyanhydride Polymerization of Glycopolypeptides That Activate Antigen-Presenting Cells through Dectin-1 and Dectin-2. Angew Chem Int Ed Engl 57:3137-3142 |
| Freeman, Spencer A; Vega, Anthony; Riedl, Magdalena et al. (2018) Transmembrane Pickets Connect Cyto- and Pericellular Skeletons Forming Barriers to Receptor Engagement. Cell 172:305-317.e10 |
| Woods, Elliot C; Kai, FuiBoon; Barnes, J Matthew et al. (2017) A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression. Elife 6: |
| Barnes, J Matthew; Przybyla, Laralynne; Weaver, Valerie M (2017) Tissue mechanics regulate brain development, homeostasis and disease. J Cell Sci 130:71-82 |
| Hudak, Jason E; Belardi, Brian; Appel, Mason J et al. (2016) Piperidine-based glycodendrons as protein N-glycan prosthetics. Bioorg Med Chem 24:4791-4800 |
| Kai, FuiBoon; Laklai, Hanane; Weaver, Valerie M (2016) Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease. Trends Cell Biol 26:486-497 |
| Xiao, Han; Woods, Elliot C; Vukojicic, Petar et al. (2016) Precision glycocalyx editing as a strategy for cancer immunotherapy. Proc Natl Acad Sci U S A 113:10304-9 |
| Freeman, Spencer A; Goyette, Jesse; Furuya, Wendy et al. (2016) Integrins Form an Expanding Diffusional Barrier that Coordinates Phagocytosis. Cell 164:128-140 |
| Bhat, Ramray; Belardi, Brian; Mori, Hidetoshi et al. (2016) Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. Proc Natl Acad Sci U S A 113:E4820-7 |
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