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

Afshar-Sterle, S; Carli, ALE; O&#39;Keefe, R; Tse, J; Fischer, S; Azimpour, AI; Baloyan, D; Elias, L; Thilakasiri, P; Patel, O; Ferguson, FM; Eissmann, MF; Chand, AL; Gray, NS; Busuttil, R; Boussioutas, A; Lucet, IS; Ernst, M; Buchert, M

Author(s): Afshar-Sterle, S; Carli, ALE; O'Keefe, R; Tse, J; Fischer, S; Azimpour, AI; Baloyan, D; Elias, L; Thilakasiri, P; Patel, O; Ferguson, FM; Eissmann, MF; Chand, AL; Gray, NS; Busuttil, R; Boussioutas, A; Lucet, IS; Ernst, M; Buchert, M;
Details: Publication Year 2024-09-17,Volume 17,Issue #854,Page eabq4888
Journal Title: Science Signaling
Abstract: 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.
Publisher: AAAS
Keywords: *Doublecortin-Like Kinases/metabolism; *Stomach Neoplasms/genetics/pathology/metabolism; Animals; Humans; *Protein Serine-Threonine Kinases/metabolism/genetics; *Intracellular Signaling Peptides and Proteins/genetics/metabolism; Mice; Cell Line, Tumor; *Disease Progression; *Phenotype; Cell Movement/genetics; Carcinogenesis/genetics/metabolism
Research Division(s): Chemical Biology
PubMed ID: 39288218
Publisher's Version: https://doi.org/10.1126/scisignal.abq4888
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-04 10:44:41

Last Modified: 2024-10-04 10:51:24