Fra-1: a safeguard protecting tumor cells from oncogenic stress

在物种和肿瘤中，我们的初步数据为转录因子fr -1 （AP-1家族成员）和MYC（与大多数癌症相关的致癌基因）的共选择/共表达提供了有力的证据，特别是在致癌KRAS的背景下。因此，我们假设Fra-1是具有超生理MYC活性的肿瘤细胞所需的“保障”，以应对MYC依赖性的致癌应激途径。使用PDAC作为真正的kras驱动的癌症，我们的目标是破译和理解Fra-1的功能，并阐明Fra-1如何防止myc依赖性的致癌应激。由于环境因素的影响，我们还将分析在kras驱动的PDAC中检测到的分子功能在kras驱动的NSCLC模型中是否明显。我们建议，对Fra-1的详细了解将允许通过靶向Fra-1的“保护”功能来开发针对kras驱动的癌症亚型的新治疗概念，我们计划在最新的PDAC人类模型系统中进行测试。

Across species and tumors our preliminary data provide robust evidence for the co-selection/co-expression of the transcription factors Fra-1, a member of the AP-1 family, and MYC, an oncogene with relevance for most cancers, especially in context of oncogenic KRAS. Therefore, we hypothesize that Fra-1 is a "safeguard" needed in tumor cells with supra-physiological MYC activity to cope with MYC-dependent oncogenic stress pathways. Using PDAC as a bona fide KRAS-driven cancer, we aim to decipher and understand the function of Fra-1 and elucidate how Fra-1 protects against MYC-dependent oncogenic stress. Since context matters, we will also analyze whether the molecular functions detected in KRAS-driven PDAC is evident in KRAS-driven NSCLC models. We propose that the detailed understanding of Fra-1 will allow to develop novel therapeutic concepts for a subtype of KRAS-driven cancers by the targeting of "safeguard" functions of Fra-1, which we plan to test in up-to-date human model systems of PDAC.