Identification and validation of BCL11A as a neural and immune vulnerability factor in pancreatic adenocarcinoma

As a highly malignant tumor, pancreatic adenocarcinoma (PAAD) has nonspecific symptoms and a poor prognosis. Previous studies have demonstrated that perineural invasion (PNI) and neurotrophic factors (NFs) play essential roles in PAAD. Nevertheless, the prognostic significance and functions of NF-related genes (NFRGs) in PAAD remain unclear. In this research, we conducted an intersection analysis utilizing differentially expressed genes (DEGs) found in the TCGA-PAAD cohort along with NFRGs from the Genecard. Using machine learning (ML) techniques, including LASSO regression, SVM-RFE and random forest algorithms, we developed a highly accurate prognostic model centered on NFRGs, ultimately pinpointing BCL11A as the crucial prognostic NFRG. Via analysis of the TCGA cohort, immunohistochemistry of 20 pairs of clinical samples and western blot of PAAD cell lines, BCL11A was found to be low-expressed in PAAD and associated with a poor prognosis. Experiments conducted both in vitro and in vivo revealed that the increased expression of BCL11A suppressed tumor growth and triggered apoptosis through endoplasmic reticulum (ER) stress. Moreover, immune infiltration analysis found increased CD8⁺ T cells in the BCL11A^high group. Flow cytometry demonstrated that overexpression of BCL11A in vivo promoted intratumoral CD8⁺ T cell infiltration and activation, and increased PD-L1 expression. Our study confirmed BCL11A as a potential biomarker of clinical prognosis, immune infiltration, and neural-tumor interactions in PAAD, and might provide new insights for diagnosis and treatment of this tumor.