p53 deficient breast cancer cells reprogram pre-adipocytes towards tumor protective immunomodulatory cells (WEP)

The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and of breast tumors, undergo transcriptional, metabolic and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an immunosuppressive tumor microenvironment, including increased abundance of myeloid-derived suppressor cells and elevated expression of the checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of several common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 loss in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 may act as a tumor suppressor. Further elucidation of the interplay between p53 mutations and adipocytes within the tumor microenvironment may suggest novel therapeutic targets for the treatment of breast cancer patients. Overall design: To investigate the effect of p53-deficient breast cancer cells on adipocyte differentiation, conditioned media from p53 wild-type and knockout WEP cancer cells was applied to differentiating 3T3-L1 adipocytes. We performed RNA-seq on 3T3-L1 cells before differentiation, after regular differentiation (as a control), and after differentiation with cancer cell conditioned media. Three replicates of each condition were taken. Pathway enrichment analysis was performed on the sequencing data from the 3T3-L1 cells.