ADAP1 promotes colorectal cancer progression and macrophage M2 polarization via ERK1/2-CCL2 signaling

Colorectal cancer (CRC) is a major malignant tumor of digestive tract with poor prognosis. Although it has been reported that the expression of ArfGAP with dual PH domains 1 (ADAP1) will increase in several cancers, what role it plays in CRC and its working mechanism are still unclear. Therefore, this study aimed to investigate the regulatory mechanism of ADAP1 in CRC. ADAP1 expression and clinical relevance were analyzed using TCGA data and colorectal cancer tissue samples. In the laboratory, ADAP1 was either overexpressed or knocked down in CRC cells, and then through cell cloning, wound healing, Western blot analysis and ELISA, the effects on cell proliferation, migration, and CCL2 secretion were assessed. THP-1 macrophages, prompted to mature with phorbol ester, were exposed to colorectal cancer cell culture media under varying experimental conditions. Subsequently, flow cytometry analysis was employed to determine whether these macrophages had undergone polarization to the M2 phenotype. In animals, we observed the effects of ADAP1 on tumor growth, ERK1/2 activation and immune cellular penetration within immunocompromised mouse xenograft tumors. ADAP1 demonstrates heightened activity in CRC, correlating with poorer patient prognosis and outcomes (p < 0.001). In the laboratory, if we increase ADAP1, it can make CRC cells enhanced distal migration by activating ERK1/2 (by approximately 2.5-fold, P < 0.01). Simultaneously, ADAP1 upregulated the production and secretion of C-C motif chemokine ligand 2 (CCL2) in an ERK1/2-dependent manner, so that macrophages can be transformed into M2. In vivo, ADAP1 overexpression accelerated tumor growth; however, this effect was attenuated by either ERK1/2 pathway inhibition or macrophage depletion. ADAP1 exacerbates colorectal cancer progression, and it also turns macrophage into M2 type by starting ERK1/2 pathway, which indicates that it may become a target for the treatment of CRC.