The small GTPase ARF3 controls metastasis and invasion modality by regulating N-cadherin levels
The small GTPase ARF3 controls metastasis and invasion modality by regulating N-cadherin levels
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DOI：
10.1101/2022.04.25.489355
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发表时间：
2022-04
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通讯作者：
Emma Sandilands;Eva C. Freckmann;Álvaro Román-Fernández;L. Mcgarry;L. Galbraith;S. Mason;Rachana Patel;Jayanthi Anand;J. Cartwright;H. Leung;K. Blyth;David M. Bryant
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作者：
Emma Sandilands;Eva C. Freckmann;Álvaro Román-Fernández;L. Mcgarry;L. Galbraith;S. Mason;Rachana Patel;Jayanthi Anand;J. Cartwright;H. Leung;K. Blyth;David M. Bryant
ARF GTP酶是膜运输的中心调节因子，其通过控制局部膜特性和重塑以促进囊泡形成来起作用。由于ARF与鸟嘌呤核苷酸交换因子（GEF）、GTP酶激活蛋白（GAP）和许多相互作用物的重叠结合，ARF GTP酶功能的解开变得复杂。冗余在多大程度上是ARF功能的一个主要因素，或者单个ARF GTPases是否对细胞行为做出独特的贡献仍不清楚。通过三维（3D）前列腺癌细胞行为的功能基因组筛选，我们探索了所有已知的ARF GTP酶，GEF，GAP和大量选择的相互作用对集体形态发生的贡献。这揭示了ARF 3 GT3调节入侵的方式，作为前导细胞领导的入侵链或集体片层运动之间的开关。在功能上，ARF 3控制侵袭方式的能力依赖于连接粘附分子N-钙粘蛋白的结合和随后的控制。在体内，ARF 3水平可作为前列腺内肿瘤移植转移的变阻器，ARF 3：N-钙粘蛋白表达可用于识别患有转移性、预后不良疾病的前列腺癌患者。我们的分析定义了ARF 3 GTdR在控制细胞在侵袭和转移过程中如何集体组织的独特功能。
ARF GTPases are central regulators of membrane trafficking that act by controlling local membrane identity and remodelling to facilitate vesicle formation. Unravelling ARF GTPase function is complicated by the overlapping association of ARFs with guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and numerous interactors. The extent to which redundancy is a major factor in ARF function or whether individual ARF GTPases make unique contributions to cellular behaviour remains unclear. Through a functional genomic screen of 3-Dimensional (3D) prostate cancer cell behaviour we explore the contribution of all known ARF GTPases, GEFs, GAPs, and a large selection of interactors to collective morphogenesis. This revealed that the ARF3 GTPase regulates the modality of invasion, acting as a switch between leader cell-led chains of invasion or collective sheet movement. Functionally, the ability of ARF3 to control invasion modality is dependent on association and subsequent control of the junctional adhesion molecule N-cadherin. In vivo, ARF3 levels acted as a rheostat for metastasis from intraprostatic tumour transplants and ARF3:N-cadherin expression can be used to identify prostate cancer patients with metastatic, poor-outcome disease. Our analysis defines a unique function for the ARF3 GTPase in controlling how cells collectively organise during invasion and metastasis.