Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment

SIMPLE SUMMARY: Mast cells are a type of immune cell that lives within organs and tissues of the body. When tumors develop in these organs, such as in prostate cancer, mast cells secrete multiple factors that can activate the tumor environment and help tumor cells to thrive. Here, we identify a gene called SAMD14 that is reduced in mast cells obtained from men with prostate cancer. We demonstrate that SAMD14 expression in mast cells can alter their secretions and promote the alignment of matrix fibers that cancer cells use to attach and move around on. By understanding how mast cells regulate their environment, we can reveal new directions of treatment that target the tumor environment as a whole, rather than just the tumor cells themselves. ABSTRACT: Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.