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

Autor: Afshar-Sterle S; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Carli ALE; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., O'Keefe R; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Tse J; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Fischer S; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Azimpour AI; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Baloyan D; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Elias L; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Thilakasiri P; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Patel O; ACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Ferguson FM; Department of Chemistry and Biochemistry and the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA., Eissmann MF; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Chand AL; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Gray NS; Department of Chemical and Systems Biology, Stanford Cancer Institute, Stanford University, Stanford, CA, USA., Busuttil R; Central Clinical School, Monash University, Melbourne, VIC, Australia.; Department of Gastroenterology, Alfred Hospital, Melbourne, VIC, Australia., Boussioutas A; Central Clinical School, Monash University, Melbourne, VIC, Australia.; Department of Gastroenterology, Alfred Hospital, Melbourne, VIC, Australia., Lucet IS; ACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Ernst M; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Buchert M; Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2024 Sep 17; Vol. 17 (854), pp. eabq4888. Date of Electronic Publication: 2024 Sep 17.
DOI: 10.1126/scisignal.abq4888
Abstrakt: 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.
Databáze: MEDLINE