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

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. Teaser DCLK1 is a druggable cancer driver of GC ### Competing Interest Statement F.M.F. and N.S.G. are inventors on a patent application related to the DCLK1 inhibitor described in this manuscript (WO/2018/075608). N. S. G. is a founder, science advisory board member (SAB) and equity holder in Gatekeeper, Syros, Petra, C4, B2S, Aduro, Jengu, Allorion, Inception and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield and Sanofi. F.M.F is a scientific co-founder and equity holder in Proximity Therapeutics, a scientific advisory board member (SAB) and equity holder in Triana Biomedicines. Fleur Ferguson is or was recently a consultant or received speaking honoraria from RA Capital, Tocris BioTechne and Plexium. The Ferguson lab receives or has received research funding from Ono Pharmaceutical Co. Ltd.