Doublecortin-like kinase 1 is a novel biomarker for prognosis and regulates growth and metastasis in basal-like breast cancer

Lv, Yuetao; Song, Ge; Wang, Rong; Di, Linlin; Wang, Jianling

doi:10.1016/j.biopha.2017.01.082

Cited by 10 publications

(5 citation statements)

References 38 publications

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“…Therefore, there is an unmet need to find new immune-related therapeutic approaches against GI cancer. Previous studies reported that DCLK1 level in colorectal, gastric, pancreatic, breast, and esophageal cancers and clear renal cell carcinoma is higher in tumor tissues compared with adjacent tissues [37,39,[69][70][71][72], and it can predict poor survival in kidney and pancreatic cancers [35,41]. Our findings again confirm that DCLK1 can be used as a prognostic biomarker for colon and gastric cancer, and extend understanding of this potential to clinically relevant subtypes.…”

Section: Discussionsupporting

confidence: 87%

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

Weygant

et al. 2020

Cancers

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Immunotherapy that has proven efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized as cancer-initiating cells and regulators of the type II immune response, and has been studied for its role in many cancers including colon and gastric cancers, but its role in tumor immunity remains unexplored. In the current study, we analyzed colon and gastric cancer RNA sequencing data from 283 and 415 patients, respectively, from The Cancer Genome Atlas (TCGA). High DCLK1 expression predicted the worse clinical outcomes in colon and gastric cancer patients and correlated with increased immune and stromal components. Further analysis indicated that DCLK1 was strongly linked to infiltration of multiple immune cell types, especially TAMs and Treg, and strongly correlated with increased CD8+ T cell inhibitors TGFB1 and CXCL12 and their receptors, suggesting it may contribute to TAM-mediated inhibition of CD8+ T cells. Interestingly, we found that DCLK1 was a prognostic biomarker in left-sided colon cancer, which has worse outcomes and demonstrates a reduced response to existing immunotherapies. In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients.

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Section: Discussionsupporting

confidence: 87%

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

Weygant

et al. 2020

Cancers

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“…DCLK1 is a microtubule binding kinase protein, which has been extensively studied in the field of neurodevelopment due to its microtubule polymerizing function of the doublecortin domains that are crucial for neuronal migration [ 74 ]. In the cancer context, DCLK1 plays a role in the cellular migration of multiple types of cancer, including colorectal, pancreatic, liver, and breast cancers [ 75 ]. Dysregulation of DCLK1 in humans and mice is associated with activated pathological cancer stages.…”

Section: Discussionmentioning

confidence: 99%

Comparative Gene Signature of (−)-Oleocanthal Formulation Treatments in Heterogeneous Triple Negative Breast Tumor Models: Oncological Therapeutic Target Insights

et al. 2021

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Triple negative breast cancer (TNBC) heterogeneity and limited therapeutic options confer its phenotypic aggressiveness. The discovery of anti-TNBC natural products with valid molecular target(s) and defined pharmacodynamic profile would facilitate their therapeutic nutraceutical use by TNBC patients. The extra-virgin olive oil (EVOO) is a key Mediterranean diet ingredient. S-(−)-Oleocanthal (OC) leads the bioactive anti-tumor EVOO phenolic ingredients. A previous study reported the solid dispersion formulated OC with (+)-xylitol (OC-X) suppressed the in vivo progression and recurrence of the TNBC MDA-MB-231 cells. This study investigates the ability of OC-X formulation to suppress the in vivo heterogeneous BC initiation and progression utilizing advanced preclinical transgenic MMTV-PyVT and TNBC PDX mouse models. Furthermore, the clustering of the gene expression profiles in MMTV-PyVT and PDX mouse tumors treated with OC-X acquired by a Clariom S microarray analysis identified the distinctly affected genes. Several affected novel signature genes identified in response to OC-X treatments and proved overlapped in both mouse and human tumor models, shedding some lights toward understanding the OC anticancer molecular mechanism and assisting in predicting prospective clinical outcomes. This study provides molecular and preclinical evidences of OC-X potential as a nutraceutical suppressing heterogeneous TNBC model and offers preliminary gene-level therapeutic mechanistic insights.

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“…Doublecortin-like kinase 1 (DCLK1) was first described in 1998 as a putative kinase, with homology to doublecortin. 1 DCLK1 upregulation is observed in various cancers, including colorectal, 2 , 3 pancreatic, 4 hepatocellular, 5 , 6 renal, 7 breast, 8 and bladder cancers, 9 along with esophageal adenocarcinoma, 10 and its expression has been shown to promote tumorigenesis. 9 , 11 , 12 , 13 , 14 DCLK1 is a marker for tumor stem cells (TSCs) in colon and pancreatic cancers, and is likely a TSC marker in other cancers.…”

Section: Introductionmentioning

confidence: 99%

DCLK1 autoinhibition and activation in tumorigenesis

Yang

Guo

et al. 2022

The Innovation

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Doublecortin-like kinase 1 (DCLK1) is upregulated in many tumors and is a marker for tumor stem cells. Accumulating evidence suggests DCLK1 constitutes a promising drug target for cancer therapy. However, the regulation of DCLK1 kinase activity is poorly understood, particularly the function of its autoinhibitory domain (AID), and, moreover, no physiological activators of DCLK1 have presently been reported. Here we determined the first DCLK1 kinase structure in the autoinhibited state and identified the neuronal calcium sensor HPCAL1 as an activator of DCLK1. The C-terminal AID functions to block the ATP-binding site and is competitive with ATP. HPCAL1 binds directly to the AID in a Ca 2+ -dependent manner, which releases the autoinhibition. We also analyzed cancer-associated mutations occurring in the AID and elucidate how these mutations disrupt DCLK1 autoinhibition to elicit kinase activity upregulation. Our results present a molecular mechanism for autoinhibition and activation of DCLK1 kinase activity and provide insights into DCLK1-associated tumorigenesis.

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Doublecortin-like kinase 1 is a novel biomarker for prognosis and regulates growth and metastasis in basal-like breast cancer

Cited by 10 publications

References 38 publications

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

Comparative Gene Signature of (−)-Oleocanthal Formulation Treatments in Heterogeneous Triple Negative Breast Tumor Models: Oncological Therapeutic Target Insights

DCLK1 autoinhibition and activation in tumorigenesis

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