Role of ALK4 in Regulating Receptor Trafficking and Pancreatic Cancer Biology

胰腺癌是一种侵袭性和难以治疗的疾病，总体5年生存率为3- 5%。的 胰腺癌的发病率正在增加，预计将成为癌症死亡的第二大原因。 5年尽管对其分子发病机制有详细的了解，但靶向治疗的影响很小 免疫疗法无效激活素受体样激酶4（ALK 4）是一种I型转化生长因子， 因子-β（TGF-β）超家族受体，其介导几种TGF-β超家族配体的信号传导。突变 35%的胰腺癌患者发生ALK 4或拷贝数丢失， 与预后较差有关。此外，ALK 4已在无偏筛选中被鉴定为基因 其破坏增强Ras介导的体内胰腺肿瘤发生。我们证明了ALK 4的缺失 表达增加I型（TβRI/ALK 5）和II型（TβRII）TGF-β受体（TβR）水平，导致增加 典型TGF-β信号传导的激活，增强EMT标志物和表型的获得，以及增加 肿瘤的侵袭和转移。我们还发现ALK 4选择性地调节细胞表面表达， 通过促进其糖基化和加工/运输到细胞表面， 高尔基带的形成/延伸，这可能是由高尔基体调节因子GOLPH 3， 肌球蛋白18 A基于这些初步结果，我们假设ALK 4功能的丧失促进了 通过促进高尔基带形成/延伸， 增加TβR受体糖基化和运输到细胞表面，增加TβR细胞表面水平， 下游信号和癌症生物学。我们进一步假设，在胰腺癌中阻断这些作用， 具有ALK 4功能丧失的癌症患者可以提供治疗益处。我们提出三个具体目标。 目的1：探讨ALK 4缺失促进TGF-β信号传导的机制，包括确定 影响高尔基带的形成/延伸。目的2：我们将确定在胰腺癌中ALK 4表达的缺失是否与胰腺癌的发生有关。 癌细胞促进胰腺癌的癌症发生和/或进展，或对吉西他滨产生耐药性 体内模型。目的3：我们将确定ALK 4缺失的胰腺癌标本是否具有增加的TGF-β 1。 β信号传导和高尔基带形成/延伸以及ALK 4的缺失是否会在 这些胰腺癌患者，这可以用于治疗效益。这些研究将定义新的 ALK 4缺失调节TGF-β信号传导和下游胰腺癌生物学的机制， 可以将ALK 4缺失确定为胰腺癌和其他癌症中抗TGF-β方法的预测生物标志物。 具有ALK 4表达突变或缺失的人类癌症。 !

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. !