A pro-metastatic secretory pathway activated by p53 loss in lung cancer

癌细胞被嵌入一个保护和滋养的“生态位”， 癌细胞通过分泌蛋白质到周围环境中而产生的环境。因为癌细胞 依靠它们的利基生存并扩散到身体的其他部位，我们认为， 抑制分泌可以抑制癌症扩散，从而提高癌症患者的寿命和质量。 生活开发这种疗法需要更好地了解癌症中分泌是如何被激活的。我们 该提案将弥补这一知识差距。在这里，我们表明，p53蛋白的损失，一个既定的驱动程序的癌症， 扩散，通过重新编程高尔基体来增强分泌，高尔基体是蛋白质运输的主要调节器， 细胞我们发现p53缺失激活了控制分泌的高尔基体蛋白复合体的形成， 已经鉴定出对肺癌生长和扩散至关重要的分泌蛋白。此外，我们有 确定了一种药物，可以阻止高尔基体蛋白复合物的形成，减少分泌，并抑制肺 癌症的生长和扩散。在本申请中，我们试图阐明分子基础， 由p53缺失驱动的分泌增加的治疗意义。在目标1中，我们建议开展研究， 阐明高尔基体蛋白复合体如何增强分泌和驱动肺癌进展。在目标2中，我们 我建议进行研究，以确定高尔基体蛋白复合物如何增加对我们现有药物的敏感性。 鉴定这些研究将提供深入了解分泌是如何在癌症中被激活的，并可能导致新的 靶向癌症患者分泌的方法。

Cancer cells are embedded in a protective and nourishing “niche”, an environment that cancer cells create by secreting proteins into their surroundings. Because cancer cells depend on their niche to survive and spread to other parts of the body, we believe that therapies designed to inhibit secretion could suppress cancer spread and thereby improve the length and quality of cancer patients' lives. Developing such therapies will require a better understanding of how secretion is activated in cancer. Our proposal will address this knowledge gap. Here we show that p53 protein loss, an established driver of cancer spread, enhances secretion by reprogramming the Golgi apparatus, a master regulator of protein transport in cells. We show that p53 loss activates the formation of a Golgi protein complex that controls secretion, and we have identified secreted proteins that are essential for lung cancer growth and spread. Furthermore, we have identified a drug that can block the formation of the Golgi protein complex, reduce secretion, and inhibit lung cancer growth and spread. In this application, we seek to elucidate the molecular underpinnings and therapeutic implications of the heightened secretion driven by p53 loss. In aim 1, we propose studies to elucidate how the Golgi protein complex enhances secretion and drives lung cancer progression. In aim 2, we propose studies to determine how the Golgi protein complex increases sensitivity to the drug we have identified. These studies will provide insight into how secretion is activated in cancer and may lead to new ways to target secretion in cancer patients.