Moore Landon L, Qu Dongfeng, Chandrekesan Parthasarathy, Pitts Kamille, May Randal, Anderson Byron E, Brown Milton, Houchen Courtney W
University of Oklahoma Health Sciences Center.
Independent Researcher.
Res Sq. 2025 Mar 11:rs.3.rs-6099914. doi: 10.21203/rs.3.rs-6099914/v1.
What drives inflammation-associated tumorigenesis and progression in pancreatic ductal adenocarcinoma (PDAC)? Doublecortin-like kinase 1 (DCLK1) is a central driver of inflammation-associated tumorigenesis, with elevated expression linked to worse clinical outcomes. Isoform 4, which lacks microtubule-binding domains but contains a unique extracellular domain (ECD), plays a pivotal role in tumor progression. We identified novel D-peptides that selectively target this ECD, significantly suppressing PDAC cell proliferation in vitro and tumor growth in xenograft models without inducing cell death. In silico modeling and binding assays revealed DCLK1 isoform 4 interacts with pro-tumorigenic proteins like plasma gelsolin (pGSN), with D-peptides modulating these interactions. These findings underscore DCLK1's non-kinase functions as a therapeutic target and highlight novel avenues for developing precision treatments aimed at halting cancer progression and improving patient outcomes.
是什么驱动胰腺导管腺癌（PDAC）中与炎症相关的肿瘤发生和进展？双皮质素样激酶1（DCLK1）是炎症相关肿瘤发生的核心驱动因素，其表达升高与较差的临床结果相关。异构体4缺乏微管结合结构域，但含有独特的细胞外结构域（ECD），在肿瘤进展中起关键作用。我们鉴定出了选择性靶向该ECD的新型D肽，可在体外显著抑制PDAC细胞增殖，并在异种移植模型中抑制肿瘤生长，且不会诱导细胞死亡。计算机模拟和结合试验表明，DCLK1异构体4与促肿瘤蛋白如血浆凝溶胶蛋白（pGSN）相互作用，而D肽可调节这些相互作用。这些发现强调了DCLK1的非激酶功能作为治疗靶点的重要性，并突出了开发旨在阻止癌症进展和改善患者预后的精准治疗新途径。
