Role of RABL6A-PP2A in neuroendocrine tumors

项目概要/摘要 神经内分泌肿瘤（NETs）是一种无法治愈的、临床上具有挑战性的恶性肿瘤，其发病率正在上升。 虽然肿瘤生长缓慢，但它们无情地发展，一旦它们成为肿瘤，就缺乏有效的治疗方法。 转移性的许多患有晚期NET的患者会死于这种疾病。更好地了解 需要驱动NET进展和转移的机制来告知新疗法并改善患者 结果。 我们发现了促进胰腺NET（PNET）发病的RABL 6A-PP 2A通路。RABL6A （RAB样GT3）在患者PNET中上调，并且是PNET增殖和存活所需的。 RABL 6A通过多种机制发挥作用，这些机制仅部分确定，包括抑制肿瘤 抑制因子（p27，RB 1）和致癌途径（MYC，AKT-mTOR）的激活。一个共同的调节器， 这些因子是蛋白磷酸酶2A（PP 2A），一种强大的肿瘤抑制因子，其在NETs中的作用尚未被证实。 被探索。我们发现RABL 6A通过抑制PP 2A激活PNTR中的AKT-mTOR信号传导。反过来， RABL 6A被PP 2A下调，尽管这两种蛋白质抑制RABL 6A的分子机制是不一致的。 彼此的功能是未知的。令人兴奋的是，特定的“PP 2A小分子激活剂”（称为SMAPs） 以RABL 6A依赖方式抑制PNET细胞增殖和存活， vivo.这些发现支持了一种新的PNET治疗策略，包括PP 2A再激活。然而，作用 RABL 6A和PP 2A在NET进展中的作用仅部分了解，它们在NET转移中的重要性 不知道。这项多PI研究利用了PI的集体知识及其独特的专业知识/ NET（Quelle）和PP 2A（Narla）中的资源，以测试RABL 6A-PP 2A 通路是NET进展和对靶向治疗反应的关键驱动因素。目标1将决定 RABL 6A-PP 2A相互调节的机制。目标2将界定以下机构的作用和相互依存关系： RABL 6A和PP 2A在NET进展和转移中的作用。目标3将确立RABL 6A的重要性- NET发病机制中的PP 2A改变和途径靶向联合治疗的疗效。 该项目将提供新的见解分子事件驱动NET进展和转移， 建立有前途的NET疗法的疗效，从而解决NET研究中的一个关键空白， 最终可以改善患者的预后。此外，这项工作建立在一个新兴的抗癌策略， 治疗（即，PP 2A的药理学再激活），并且可能具有超出NET的广泛的癌症相关性 考虑到RABL 6A过表达和PP 2A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.