MYC is a powerful transcription factor overexpressed in many human cancers including B cell and prostate cancers. Antibody therapeutics are exciting opportunities to attack cancers but require knowledge of surface proteins that change due to oncogene expression. To identify how MYC overexpression remodels the cell surface proteome in a cell autologous fashion and in different cell types, we investigated the impact of MYC overexpression on 800 surface proteins in three isogenic model cell lines either of B cell or prostate cell origin engineered to have high or low MYC levels. We found that MYC overexpression resulted in dramatic remodeling (both up- and down-regulation) of the cell surfaceome in a cell type-dependent fashion. We found systematic and large increases in distinct sets of >80 transporters including nucleoside transporters and nutrient transporters making cells more sensitive to toxic nucleoside analogs like cytarabine, commonly used for treating hematological cancers. Paradoxically, MYC overexpression also increased expression of surface proteins driving cell turnover such as TNFRSF10B, also known as death receptor 5, and immune cell attacking signals such as the natural killer cell activating ligand NCR3LG1, also known as B7-H6. We generated recombinant antibodies to these two targets and verified their up-regulation in MYC overexpression cell lines and showed they were sensitive to bispecific T cell engagers (BiTEs). Our studies demonstrate how MYC overexpression leads to dramatic bidirectional remodeling of the surfaceome in a cell type-dependent but functionally convergent fashion and identify surface targets or combinations thereof as possible candidates for cytotoxic metabolite or immunotherapy.

MYC 是一种强大的转录因子，在许多人类癌症（包括 B 细胞癌和前列腺癌）中过表达。抗体疗法是攻击癌症的令人兴奋的机会，但需要了解因癌基因表达而变化的表面蛋白。为了确定 MYC 过表达如何以细胞自体方式和在不同细胞类型中重塑细胞表面蛋白质组，我们研究了 MYC 过表达对 B 细胞或前列腺细胞来源的三种同基因模型细胞系中 800 种表面蛋白的影响，这些细胞系被设计为具有高或 MYC 水平低。我们发现 MYC 过度表达导致细胞表面组以细胞类型依赖性方式发生戏剧性重塑（上调和下调）。我们发现超过 80 个转运蛋白组的系统性大幅增加，包括核苷转运蛋白和营养转运蛋白，使细胞对有毒核苷类似物（如阿糖胞苷）更加敏感，阿糖胞苷通常用于治疗血液癌症。矛盾的是，MYC 过度表达还增加了驱动细胞更新的表面蛋白（例如 TNFRSF10B，也称为死亡受体 5）和免疫细胞攻击信号（例如自然杀伤细胞激活配体 NCR3LG1，也称为 B7-H6）的表达。我们针对这两个靶标生成了重组抗体，并验证了它们在 MYC 过表达细胞系中的上调，并表明它们对双特异性 T 细胞接合器 (BiTE) 敏感。我们的研究证明了 MYC 过表达如何以细胞类型依赖性但功能收敛的方式导致表面组的戏剧性双向重塑，并确定表面靶标或其组合作为细胞毒性代谢物或免疫治疗的可能候选者。