DCLK1 induces a pro-tumorigenic phenotype to drive gastric cancer progression.

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 (MKN1^D511N). MKN1^D511N cells also had reduced in vitro migratory potential and stemness compared with control cells. Mice orthotopically grafted with MKN1 cells overexpressing DCLK1 (MKN1^DCLK1) 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 MKN1^DCLK1 cells. Moreover, inhibition of the kinase activity of DCLK1 or the expression of DCLK1^D511N reversed the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a broadly acting and potentially targetable promoter of GC. Editor's summary: The serine/threonine kinase DCLK1 is a putative cancer stem cell marker that is associated with the progression of gastric cancers. Afshar-Sterle et al. found that mutating the kinase domain of DCLK1 or inhibiting its kinase activity reduced tumor growth, abundance of markers of stromal remodeling, and induction of epithelial-to-mesenchymal transition (EMT). The tumor-intrinsic and -extrinsic effects of DCLK1 at least partially depended on increased amounts of CXCL12, which correlated with DCLK1 abundance and acted downstream of DCLK1. These results shed light on the mechanistic contribution of DCLK1 in shaping gastric cancer progression. —Amy E. Baek [ABSTRACT FROM AUTHOR]