Arner Emily N, Alzhanova Dina, Westcott Jill M, Hinz Stefan, Tiron Crina Elena, Blø Magnus, Mai Anja, Virtakoivu Reetta, Phinney Natalie, Nord Silje, Aguilera Kristina Y, Rizvi Ali, Toombs Jason E, Reese Tanner C, Fey Vidal, Micklem David, Gausdal Gro, Ivaska Johanna, Lorens James B, Brekken Rolf A
Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sci Signal. 2024 Dec 17;17(867):eado6057. doi: 10.1126/scisignal.ado6057.
The receptor tyrosine kinase AXL promotes tumor progression, metastasis, and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we found that activation of AXL resulted in the phosphorylation of TANK-binding kinase 1 (TBK1) and the downstream activation of AKT3 and Snail, a transcription factor critical for EMT. Mechanistically, we showed that TBK1 directly bound to and phosphorylated AKT3 in a manner dependent on the multiprotein complex mTORC1. Upon activation, AKT3 interacted with and promoted the nuclear accumulation of Snail, which led to increased EMT as assessed by marker abundance. In human pancreatic ductal adenocarcinoma tissue, nuclear AKT3 colocalized with Snail and correlated with worse clinical outcomes. Primary mouse pancreatic cancer cells deficient in AKT3 showed reduced metastatic spread in vivo, suggesting selective AKT3 inhibition as a potential therapeutic avenue for targeting EMT in aggressive cancers.
受体酪氨酸激酶AXL通过诱导上皮-间质转化（EMT）促进肿瘤进展、转移和治疗抗性。在此，我们发现AXL的激活导致TANK结合激酶1（TBK1）磷酸化以及AKT3和Snail的下游激活，Snail是一种对EMT至关重要的转录因子。从机制上讲，我们表明TBK1以依赖于多蛋白复合物mTORC1的方式直接结合并磷酸化AKT3。激活后，AKT3与Snail相互作用并促进其核积累，通过标志物丰度评估，这导致EMT增加。在人胰腺导管腺癌组织中，核AKT3与Snail共定位，并与更差的临床结果相关。缺乏AKT3的原发性小鼠胰腺癌细胞在体内显示出转移扩散减少，提示选择性抑制AKT3作为在侵袭性癌症中靶向EMT的潜在治疗途径。
