Role of ALK4 in Regulating Receptor Trafficking and Pancreatic Cancer Biology

ALK4 在调节受体贩运和胰腺癌生物学中的作用

基本信息

批准号：
10682545
负责人：
GERARD C BLOBE
金额：
$ 39.46万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682545
关键词：
Activin Receptor Biological Process Cancer Biology Cancer Etiology Cell Surface Receptors Cell surface Cessation of life Chemoresistance Data Disease Event Funding GOLPH3 gene Genes Glucosamine Golgi Apparatus Growth Human Immunotherapy In Vitro Incidence Invaded KRASG12D Knock-out Knowledge Ligands Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Molecular Mutate Mutation Myosin ATPase Neoplasm Metastasis Pathogenesis Pathway interactions Phenotype Prognosis Public Health Regulation Resistance Role Signal Pathway Signal Transduction Solid Neoplasm Somatic Mutation Specimen Structure Survival Rate TGF-beta type I receptor Therapeutic Transforming Growth Factor beta Transforming Growth Factor beta Receptors cancer cell cancer initiation derepression gemcitabine glycosylation in vivo in vivo Model inhibitor insight loss of function mouse model novel pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic tumorigenesis predictive marker receptor receptor expression receptor-mediated signaling targeted treatment trafficking tumor progression

项目摘要

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. !

胰腺癌是一种侵袭性且难以治疗的疾病，总体 5 年生存率为 3-5%。胰腺癌的发病率正在上升，预计将成为全球癌症死亡的第二大原因尽管对其分子发病机制有了详细的了解，但靶向治疗的影响却微乎其微。激活素受体样激酶 4 (ALK4) 是一种 I 型转化生长，免疫治疗无效。因子-β (TGF-β) 超家族受体，介导多种 TGF-β 超家族配体的信号传导。 35% 的胰腺癌患者发生 ALK4 或拷贝数丢失，并伴有 ALK4 表达丢失此外，ALK4 已在公正的筛选中被鉴定为一个基因。我们证明 ALK4 的缺失会增强 Ras 介导的胰腺肿瘤发生。表达增加 I 型 (TβRI/ALK5) 和 II 型 (TβRII) TGF-β 受体 (TβR) 水平，导致激活经典 TGF-β 信号传导，增强 EMT 标记和表型的获取，并增加我们还发现ALK4选择性地调节细胞表面的表达。通过对受体的影响来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，可能受到高尔基调节因子 GOLPH3 的相互作用的调节，基于这些初步结果，我们发现 ALK4 功能的丧失会促进肌球蛋白 18A 的发生。通过促进高尔基带形成/延伸来提高胰腺癌进展和化疗耐药性增加 TβR 受体糖基化和运输到细胞表面，增加 TβR 细胞表面水平，我们进一步研究阻断胰腺中的这些效应。我们提出了三个具体目标。目标 1：将探索 ALK4 缺失促进 TGF-β 信号转导的机制，包括定义对高尔基带形成/延伸的影响目标 2：我们将确定胰腺中 ALK4 表达是否缺失。癌细胞促进癌症的发生和/或进展，或胰腺癌对吉西他滨的耐药性目标 3：我们将确定 ALK4 缺失的胰腺癌标本中 TGF-β 是否增加。 β 信号传导和高尔基带形成/延伸和丢失 ALK4 是否会在以下方面产生独特的漏洞这些研究将确定新的治疗益处。 ALK4 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 ALK4 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 ALK4 表达突变或缺失的人类癌症。！