Paracrine Signaling in Glioma: Bioenergetics Heterogeneity and Chemoresistance

异质结是肿瘤的标志，在恶性肿瘤的结局中起着至关重要的作用， 因为它不仅会混淆诊断，还会挑战有效疗法的设计。 肿瘤作为一种结构上异质的系统， 在脉管系统、宿主浸润和结缔组织成分中， 了解生物能量异质性以及癌细胞如何依赖于不同的 生物能量途径相互作用以驱动肿瘤生长。在本申请中，我们建议 测试糖酵解化学敏感性胶质瘤细胞抑制扩增和生长的假设 通过旁分泌机制， 分泌型胰岛素生长因子结合蛋白6（IGFBP6）。提出了两个目标：1） 表征糖酵解化学敏感细胞和Oxphos之间的旁分泌途径， 依赖性化学抗性细胞，和2）确定TMZ处理对细胞增殖的影响。 Oxygen依赖性化学抗性细胞的富集。在这两个目标中，我们将使用遗传和 在人细胞系和患者来源的xenoline模型中的药理学方法。工作 提出的，预计将确定一种新的旁分泌途径之间的oxidase依赖性 化学抗性和糖酵解化学敏感胶质瘤细胞，并证明了 TMZ通过阻断这种旁分泌调节，扩大了耐药细胞的库， 导致致瘤性增加。如果成功，这项研究将定义一种新的肿瘤生长 模型，其中肿瘤内生物能量异质性在肿瘤的生长中起关键作用。 肿瘤整体重要的是，我们建议标准治疗方式可以选择性地 摧毁这种结构化的人口，促进随后的发展。因此，委员会认为， 通过维持而不是破坏这种抑制性肿瘤层来控制肿瘤进展 可能比传统的高剂量密度治疗更有效， 尽可能多的肿瘤细胞。

Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. Much attention has been placed on tumors as architecturally heterogeneous systems that differ regionally in vasculature, host infiltrates, and connective tissue components, but far less is known about bioenergetic heterogeneity and how cancer cells dependent on different bioenergetic pathways interact together to drive tumor growth. In this application, we propose to test the hypothesis that glycolytic chemosensitive glioma cells inhibit the expansion and growth of Oxphos-dependent chemoresistant glioma cells through a paracrine mechanism involving secreted insulin growth factor binding protein 6 (IGFBP6). Two aims are proposed to: 1) Characterize the paracrine pathway between glycolytic chemosensitive cells and Oxphos- dependent chemoresistant cells, and 2) Determine the effect of TMZ treatment on the enrichment of Oxphos-dependent chemoresistant cells. In both aims, we will use genetic and pharmacologic approaches in human cell lines and patient–derived xenoline models. The work proposed is expected to identify a novel paracrine pathway between Oxphos-dependent chemoresistant and glycolytic chemosensitive glioma cells and demonstrate that standard of care TMZ, by interrupting this paracrine regulation, expands the pool of chemoresistant cells, leading to increased tumorigenicity. If successful, this study will define a novel tumor growth model where by intratumoral bioenergetic heterogeneity is critically involved in the growth of the tumor as a whole. Importantly, we propose that standard treatment modalities may selectively destroy this structured population and facilitate subsequent progression. Consequently, controlling tumor progression by maintaining rather than destroying this suppressive tumor layer may be more effective than conventional high-dose density therapy that aims to kill the maximum possible number of tumor cells.