The kinase activity of the cancer stem cell marker DCLK1 drives gastric cancer progression by reprogramming the stromal tumor landscape

Abstract

Gastric cancer (GC) is the 3rd leading cause of cancer mortality worldwide, therefore providing novel diagnostic and treatment options is crucial for at risk groups. The serine/threonine kinase doublecortin-like kinase 1 (DCLK1) is a proposed driver of GC with frequent amplification and somatic missense mutations yet the molecular mechanism how DCLK1 mediates tumorigenesis is poorly understood. We report how DCLK1 expression orchestrates complementary cancer cell intrinsic and extrinsic processes leading to a comprehensive pro-invasive and pro-metastatic reprogramming of cancer cells and tumor stroma in a DCLK1 kinase-dependent manner. Mechanistically, we identify the chemokine CXCL12 as a key promoter of the pro-tumorigenic properties downstream of DCLK1. Importantly, inhibition of the DCLK1 kinase domain reverses the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a promising, targetable master regulator of GC.TeaserDCLK1 is a druggable cancer driver of GC

Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis

“…Many studies have shown that the overexpression of DCLK1 in cancer cells results in induction of EMT, stemness and increased cell migration and invasion, which can be reversed with small molecules targeting the kinase domain of DCLK1 [ 31 , 34 , 35 , 46 , 47 , 126 ]. In addition, targeting DCLK1 with anti-DCLK1 monoclonal antibody (CBT-15) or siRNAs showed promising results in reducing tumor burden, cancer stemness, invasion, and metastasis [ 31 , 35 , 41 , 46 , 47 , 48 , 49 , 50 , 51 , 54 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 ]. It remains to be shown whether such anti-DCLK1 targeting approaches are equally effective in the context of the various DCLK1 missense mutations that promote tumorigenesis.…”