Role of ALK4 in Regulating Receptor Trafficking and Pancreatic Cancer Biology

胰腺癌是一种侵袭性很强且难以治疗的疾病，总体5年存活率为3-5%。这个 胰腺癌的发病率正在上升，预计它将成为#年癌症死亡的第二大原因。 五年了。尽管对其分子发病机制有详细了解，但靶向治疗的影响微乎其微。 免疫治疗也一直没有效果。激活素受体样激酶4(ALK4)是一种I型转化生长因子 因子-β(转化生长因子-β)超家族受体，介导多种转化生长因子-β超家族配体的信号传导。突变 在35%的胰腺癌患者中发生ALK4拷贝数丢失，并伴有ALK4表达丢失 与较差的预后有关。此外，ALK4已经在无偏见的筛查中被确定为一种基因 它的破坏增强了RAS介导的体内胰腺肿瘤的发生。我们证明了ALK4的丧失 表达增加I型(TβRI/ALK5)和II型(TβRII)转化生长因子-β受体(TβR)水平，导致 激活规范的转化生长因子-β信号，增强对EMT标志物和表型的获取，并增加 肿瘤的体内侵袭和转移。我们还发现，ALK4选择性地调节细胞表面的表达 通过促进受体的糖基化和加工/运输到细胞表面，通过影响 高尔基带形成/延伸，其可由高尔基调节剂，GOLPH3， 肌球蛋白18A。基于这些初步结果，我们假设ALK4功能的丧失促进了 通过促进高尔基体形成/延伸至 增加TβR受体糖基化和转运到细胞表面，增加TβR细胞表面水平， 下游信号与癌症生物学。我们进一步假设，在胰腺中阻断这些效应 ALK4功能丧失的癌症患者可能提供治疗上的好处。我们提出了三个具体目标。 目的1：探讨ALK4缺失促进转化生长因子-β信号转导的机制，包括定义 对高尔基带形成/延伸的影响。目的2：我们将确定ALK4在胰腺组织中的表达缺失 癌细胞促进胰腺癌的启动和/或进展，或对吉西他滨的耐药性 活体模型。目的3：我们将确定ALK4缺失的胰腺癌标本是否增加了转化生长因子-1。 β信号和高尔基带的形成/延伸，以及ALK4的丢失是否在 这些胰腺癌患者，可以利用这些治疗效益。这些研究将定义小说 ALK4缺失调控转化生长因子-β信号转导及下游胰腺癌生物学行为的机制 可以确定alk4丢失作为胰腺癌和其他疾病抗转化生长因子-β治疗方法的预测生物标志物 ALK4基因突变或表达缺失的人类癌症。 好了！

Pancreatic cancer is an aggressive and difficult to treat disease, with an overall 5-year survival rate of 3-5%. The incidence of pancreatic cancer is increasing and it is projected to be the 2nd leading cause of cancer death within 5 years. Despite detailed knowledge of its molecular pathogenesis, targeted therapies have had minimal impact and immunotherapy has been ineffective. Activin receptor-like kinase 4 (ALK4) is a type I transforming growth factor-β (TGF-β) superfamily receptor that mediates signaling for several TGF-β superfamily ligands. Mutation or copy number loss of ALK4 occurs in 35% of pancreatic cancer patients, with loss of ALK4 expression associated with a poorer prognosis. In addition, ALK4 has been identified in an unbiased screen as a gene whose disruption enhances Ras mediated pancreatic tumorigenesis in vivo. We demonstrate that loss of ALK4 expression increases type I (TβRI/ALK5) and type II (TβRII) TGF-β receptor (TβR) levels, leading to increased activation of canonical TGF-β signaling, enhanced acquisition of EMT markers and phenotypes, and increased cancer invasion and metastasis in vivo. We also find that ALK4 selectively regulates the cell surface expression of receptors by promoting their glycosylation and processing/trafficking to the cell surface through effects on Golgi ribbon formation/extension, which may be regulated by the interaction of the Golgi regulator, GOLPH3, with myosin 18A. Based on these preliminary results, we hypothesize that loss of ALK4 function promotes pancreatic cancer progression and chemotherapy resistance by promoting Golgi ribbon formation/extension to increase TβR receptor glycosylation and trafficking to the cell surface, increasing TβR cell surface levels, downstream signaling and cancer biology. We further hypothesize that blocking these effects in pancreatic cancer patients with loss of ALK4 function may provide therapeutic benefit. We propose three Specific Aims. Aim 1: The mechanism by which loss of ALK4 promotes TGF-β signaling will be explored including defining effects on Golgi ribbon formation/extension. Aim 2: We will define whether loss of ALK4 expression in pancreatic cancer cells facilitates cancer initiation and/or progression, or resistance to gemcitabine in pancreatic cancer models in vivo. Aim 3: We will define whether pancreatic cancer specimens with ALK4 loss have increased TGF- β signaling and Golgi ribbon formation/extension and whether loss of ALK4 creates unique vulnerabilities in these pancreatic cancer patients, which can be exploited for therapeutic benefit. These studies will define novel mechanisms by which ALK4 loss regulates TGF-β signaling and downstream pancreatic cancer biology and could identify ALK4 loss as a predictive biomarker for anti-TGF-β approaches in pancreatic cancer and other human cancers with mutation or loss of ALK4 expression. !