CALB2 facilitates macrophage M2 polarization to promote the growth and metastasis of pancreatic adenocarcinoma.

Tumor-associated macrophages mainly differentiate into M2 phenotypes, which secrete cytokines that reshape the tumor microenvironment and promote tumor progression. This study was to explore the mechanism of CALB2 in M2 polarization and pancreatic adenocarcinoma (PAAD). Clinical tissue samples of PAAD were collected, followed by detection of WTAP, FOSL1, and CALB2 expression. The correlation between WTAP and FOSL1 or between FOSL1 and CALB2 was analyzed. THP1 cells were induced into M0 macrophages, followed by plasmid transfection and induction of M2-type macrophages. After macrophages were co-cultured with PAAD cells, functional experiments were designed to evaluate PAAD cell malignant behaviors. A transplantation tumor model and a liver metastasis model were established to assess tumor growth and metastasis. High expression of WTAP, FOSL1, and CALB2 was found in PAAD tissues and M2-type macrophages. WTAP positively linked with FOSL1, so as FOSL1 and CALB2. Mechanistically, WTAP enhanced m6A modification of FOSL1 to promote its expression, and FOSL1 promoted CALB2 transcription. Knockdown of WTAP, FOSL1, or CALB2 in macrophages inhibited PAAD cell malignant behaviors, which could be reversed by CALB2 upregulation. WTAP knockdown restrained the growth and metastasis of PAAD in nude mice via the FOSL1/CALB2 axis. In conclusion, WTAP increased the m6A level of FOSL1, activated CALB2 transcription, and promoted M2 polarization of macrophages, thereby promoting the growth and metastasis of PAAD.