Role of RABL6A-PP2A in neuroendocrine tumors

项目摘要/摘要 神经内分泌肿瘤(NETs)是一种无法治愈的、具有临床挑战性的恶性肿瘤，其发病率正在上升。 尽管肿瘤生长缓慢，但一旦形成，它们就会无情地发展，缺乏有效的治疗方法 转移性的。许多患有高级NETS的患者将死于他们的疾病。更好地理解 需要驱动净进展和转移的机制来提供新的治疗方法和改善患者 结果。 我们发现了促进胰腺网络(PNET)发病的RABL6A-PP2A通路。RABL6A (RAB样GTPase)在患者PNETs中上调，是PNET增殖和生存所必需的。 RABL6A通过多种机制发挥作用，这些机制只有一部分被确定，包括抑制肿瘤 抑制子(p27、RB1)和致癌通路的激活(MYC、AKT-mTOR)。一个共同的监管者 这些因子就是蛋白磷酸酶2A(PP2A)，它是一种强大的肿瘤抑制因子，其在NETs中的作用尚未 已经被探索过了。我们发现RABL6A通过抑制PP2A激活PNETs中的AKT-mTOR信号。反过来, RABL6A被PP2A下调，尽管这两种蛋白抑制RABL6A的分子机制 彼此的功能是未知的。令人兴奋的是，特定的PP2A小分子激活剂(称为SMAP) 以RABL6A依赖的方式抑制PNET细胞的增殖和存活，并消除肿瘤生长 活着。这些发现支持了一种涉及PP2A重新激活的PNET治疗的新策略。然而，这个角色 RABL6A和PP2A在净进展中的作用仅被部分了解，它们在净转移中的重要性是 不知道。这项多PI研究利用了两个PI的集体知识及其独特的专业知识/ 在网络(Quelle)和PP2A(Narla)中的资源，以检验RABL6A-PP2A的中心假设 通路是靶向治疗净进展和反应的关键驱动因素。目标一号将决定 RABL6A-PP2A的相互调控机制。目标2将定义以下各项的作用和相互依存关系 RABL6A和PP2A与肿瘤的净进展和转移目标3将确定RABL6A的重要性- Net发病机制中PP2A的改变和通路靶向联合治疗的疗效。 该项目将为推动净进展和转移的分子事件提供新的见解，同时 确定前景看好的网络疗法的有效性，从而解决网络研究中的一个关键差距 可能最终会改善患者的预后。此外，这项工作建立在一种新兴的抗癌战略之上 治疗(即，PP2A的药理学再激活)，并可能在网络之外与广泛的癌症相关 鉴于RABL6A过表达和PP2A失活在其他肿瘤类型中的重要性。

Project Summary / Abstract Neuroendocrine tumors (NETs) are incurable, clinically challenging malignancies that are rising in incidence. Although tumors grow slowly, they progress relentlessly and lack effective therapies once they become metastatic. Many patients with advanced NETs will die from their disease. Greater understanding of mechanisms driving NET progression and metastasis is needed to inform new therapies and improve patient outcomes. We discovered a RABL6A-PP2A pathway that promotes pancreatic NET (PNET) pathogenesis. RABL6A (RAB-like GTPase) is upregulated in patient PNETs and is required for PNET proliferation and survival. RABL6A acts through multiple mechanisms that are only partly defined, including inhibition of tumor suppressors (p27, RB1) and activation of oncogenic pathways (MYC, AKT-mTOR). A common regulator of all those factors is protein phosphatase 2A (PP2A), a powerful tumor suppressor whose role in NETs has not been explored. We found that RABL6A activates AKT-mTOR signaling in PNETs by inhibiting PP2A. In turn, RABL6A is down regulated by PP2A although the molecular mechanism by which these two proteins inhibit each other's function is unknown. Excitingly, specific `small molecule activators of PP2A' (called SMAPs) suppress PNET cell proliferation and survival in a RABL6A-dependent manner and abolish tumor growth in vivo. These findings support a novel strategy for PNET therapy involving PP2A reactivation. However, the role of RABL6A and PP2A in NET progression is only partly understood and their importance in NET metastasis is not known. This multi-PI study draws upon the collective knowledge of both PIs and their unique expertise / resources in NETs (Quelle) and PP2A (Narla) to test the central hypothesis that the RABL6A-PP2A pathway is a critical driver of NET progression and response to targeted therapies. Aim 1 will determine the mechanisms of RABL6A-PP2A reciprocal regulation. Aim 2 will define the roles and interdependence of RABL6A and PP2A in NET progression and metastasis. Aim 3 will establish the importance of the RABL6A- PP2A alterations in NET pathogenesis and the efficacy of pathway targeted combination therapies. This project will provide new insights into molecular events driving NET progression and metastasis while establishing the efficacy of promising NET therapeutics, thus addressing a critical gap in NET research that may ultimately improve patient outcomes. Moreover, this work builds upon an emerging strategy for anticancer therapy (i.e., pharmacological reactivation of PP2A), and may have broad cancer relevance beyond NETs given the importance of RABL6A overexpression and PP2A inactivation in other tumor types.