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<sup>D511N</sup>). MKN1<sup>D511N</sup> cells also had reduced in vitro migratory potential and stemness compared with control cells. Mice orthotopically grafted with MKN1 cells overexpressing DCLK1 (MKN1<sup>DCLK1</sup>) 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<sup>DCLK1</sup> cells. Moreover, inhibition of the kinase activity of DCLK1 or the expression of DCLK1<sup>D511N</sup> reversed the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a broadly acting and potentially targetable promoter of GC.
Authors
- Isabelle S. Lucet (ORCID: https://orcid.org/0000-0002-8563-8753)
- Janson W.T. Tse (ORCID: https://orcid.org/0000-0002-4592-1220)
- Nathanael S. Gray (ORCID: https://orcid.org/0000-0001-5354-7403)
- Fleur M. Ferguson (ORCID: https://orcid.org/0000-0003-4091-7617)
- Pathum Thilakasiri (ORCID: https://orcid.org/0000-0001-8673-1290)
- Ryan O’Keefe (ORCID: https://orcid.org/0000-0002-8527-2165)
- Onisha Patel (ORCID: https://orcid.org/0000-0001-6701-7139)
- Ashwini L. Chand (ORCID: https://orcid.org/0000-0002-1245-729X)
- Shoukat Afshar‐Sterle (ORCID: https://orcid.org/0000-0003-2678-7297)
- Moritz F. Eissmann (ORCID: https://orcid.org/0000-0002-2855-0616)
- Annalisa L. E. Carli (ORCID: https://orcid.org/0000-0003-0312-1097)
- David Baloyan (ORCID: https://orcid.org/0000-0002-9153-263X)
- Michael Büchert (ORCID: https://orcid.org/0000-0003-2672-0148)
- Alexander I. Azimpour
- Lena Elias (ORCID: https://orcid.org/0000-0002-0248-1034)
- Rita A. Busuttil (ORCID: https://orcid.org/0000-0002-2261-3495)
- Matthias Ernst (ORCID: https://orcid.org/0000-0002-6399-1177)
- Alex Boussioutas (ORCID: https://orcid.org/0000-0002-8109-6897)
- Stefanie Fischer
Institutions
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- La Trobe University (AU)
- The Alfred Hospital (AU)
- University of California San Diego (US)
- Olivia Newton-John Cancer Wellness & Research Centre (AU)
- Monash University (AU)
- University of Montana (US)
- Stanford University (US)
Publication Details
- Journal
- Science Signaling
- Published
- 2024-09-17
- DOI
- https://doi.org/10.1126/scisignal.abq4888
- Citations
- 6
- Primary Topic
- Caveolin-1 and cellular processes
- Type
- article
- Field-Weighted Citation Impact
- 1.96