双皮质素样激酶 1 (DCLK1) 被认为是胃癌 (GC) 的驱动因素，可磷酸化丝氨酸和苏氨酸残基。在这里，我们表明 DCLK1 的激酶活性协调了癌细胞的内在和外在过程，导致 GC 细胞的促侵袭和促转移重编程。抑制 DCLK1 激酶活性可减少小鼠体内 MKN1 人胃癌细胞形成的皮下异种移植肿瘤的生长，并降低基质标志物 α-Sma、波形蛋白和胶原蛋白的丰度。在由表达激酶失活 DCLK1 突变体 (MKN1D511N) 的 MKN1 细胞形成的异种移植肿瘤的小鼠中也观察到了类似的效果。与对照细胞相比，MKN1D511N 细胞的体外迁移潜力和干性也降低。与移植对照 MKN1 细胞的小鼠相比，原位移植过表达 DCLK1 (MKN1DCLK1) 的 MKN1 细胞的小鼠表现出更高的侵袭性，并且肺转移的发生率更高。从机制上讲，我们发现趋化因子 CXCL12 在培养的 MKN1 细胞和皮下植入 MKN1DCLK1 细胞形成的胃肿瘤的小鼠中作用于 DCLK1 下游。此外，抑制 DCLK1 激酶活性或 DCLK1D511N 表达可逆转促肿瘤发生和促转移表型。总之，这项研究确立了 DCLK1 作为 GC 的一种广泛作用且具有潜在靶向性的启动子。

Doublecortin-like kinase 1 (DCLK1) is a proposed driver of gastric cancer (GC) that phosphorylates serine and threonine residues. Here, we showed that the kinase activity of DCLK1 orchestrated cancer cell-intrinsic and-extrinsic processes that led to pro-invasive and pro-metastatic reprogramming of GC cells. Inhibition of the kinase activity of DCLK1 reduced the growth of subcutaneous xenograft tumors formed from MKN1 human gastric carcinoma cells in mice and decreased the abundance of the stromal markers α-Sma, vimentin, and collagen. Similar effects were seen in mice with xenograft tumors formed from MKN1 cells expressing a kinase-inactive DCLK1 mutant (MKN1D511N). MKN1D511N cells also had reduced in vitro migratory potential and stemness compared with control cells. Mice orthotopically grafted with MKN1 cells overexpressing DCLK1 (MKN1DCLK1) showed increased invasiveness and had a greater incidence of lung metastases compared with those grafted with control MKN1 cells. Mechanistically, we showed that the chemokine CXCL12 acted downstream of DCLK1 in cultured MKN1 cells and in mice subcutaneously implanted with gastric tumors formed by MKN1DCLK1 cells. Moreover, inhibition of the kinase activity of DCLK1 or the expression of DCLK1D511N reversed the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a broadly acting and potentially targetable promoter of GC.