Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment

Abstract

Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.

NEAT1 as a competing endogenous RNA in tumorigenesis of various cancers: Role, mechanism and therapeutic potential

“…Hodgkin's lymphoma (HL) is the most common malignant lymphoma originating in the lymphoid hematopoietic system, especially in young adults [111]. Fan et al [112] showed that NEAT1 expression was significantly enhanced in HL tissues and cell lines, and NEAT1 downregulation resulted in inhibition of HL cell proliferation and invasion through the downregulation of doublecortin-like kinase 1 (DCLK1), an accelerator in tumor cell invasion, metastasis, and EMT [113], via interaction with miR-448.…”

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma

“…It was suggested that DCLK1 regulates migration, invasion and cell motility via activation of EMT (43), an important process for cancer initiation, cancer metastasis, and secondary tumor formation. However, expression of DCLK1 was also associated with impaired DNA repair (57,58), upregulation of WNT/b-catenin (59,60), RAS (13,61), PI3K/AKT (62) and VEGF (63,64) signaling, suggesting a multifaceted role of DCLK1 in cancer initiation and progression. Concordantly, our analysis of TCGA-HNSC dataset indicates that in HNSCC, tumors expressing higher DCLK1 mRNA levels were enriched for pathways that have been implicated in the EMT and CSC maintenance (such as NOTCH, WNT, TGFb, and hedgehog signaling), as well as for RAS and angiogenesis cascades.…”

The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

“…Salient developments in profiling CSCs based on their physiological and functional properties in PC has expanded the directory of inherent CSC markers such as overexpression of core stem cell transcription factors Oct4, Sox2, and Nanog [124], expression of doublecortin and Ca2 + /calmodulindependent kinase-like 1 (DCLK1) [125], and that of cell surface receptor leucine-rich repeat-containing G proteincoupled receptor 5 (Lgr5) [126]. DCLK1 has recently gained widespread recognition as a CSC marker in the pancreatic, colon, and other cancers [127], besides being an accepted tuft cell marker in the small intestine [127,128]. Studies have identified morphologically and functionally distinct subpopulations of tumorinitiating PC cells, in preinvasive (PanIN) and invasive pancreatic neoplasms, marked by the expression of DCLK1 and CSC-like properties [116].…”

“…DCLK1 has recently gained widespread recognition as a CSC marker in the pancreatic, colon, and other cancers [ 127 ], besides being an accepted tuft cell marker in the small intestine [ 127 , 128 ]. Studies have identified morphologically and functionally distinct subpopulations of tumor-initiating PC cells, in preinvasive (PanIN) and invasive pancreatic neoplasms, marked by the expression of DCLK1 and CSC-like properties [ 116 ].…”