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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. 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]

IL11 is a member of the IL6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130), to elicit biological responses via the JAK/STAT signaling pathway. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4 + T cell-mediated antitumor responses. Absence of IL11 signaling impaired tumor growth in a sporadic mouse model of colon cancer and syngeneic allograft models of colon cancer. Adoptive bone marrow transfer experiments and in vivo depletion studies demonstrated that the tumor-promoting activity of IL11 was mediated through its suppressive effect on host CD4 + T cells in the tumor microenvironment. Indeed, when compared with Il11ra -proficient CD4 + T cells associated with MC38 tumors, their Il11ra -deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFNγ and TNFα. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFNγ, TNFα, IL6, and IL12p70) by CD4 + T cells in vitro , which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RA high tumors showed less IFNG and CD4 expression than IL11RA low tumors. Therefore, our results ascribe a tumor cell-extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokine-based therapy. See related Spotlight by van der Burg, p. 724 ., (©2021 American Association for Cancer Research.)