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

Linda K H Teng,Cheng Huang,Ralf B Schittenhelm,Mitchell G Lawrence,Michelle Richards,Shivakumar Keerthikumar,Brooke A Pereira,Luc Furic,Renea A Taylor,Gail P Risbridger,Sophie N Lee,David L Goode,Stuart J Ellem,Birunthi Niranjan,Natalie L Lister

doi:10.3390/cancers13061237

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.

Highlights

Prostate cancer is the second most commonly diagnosed male cancer worldwide, and the fifth leading cause of cancer death in men [1]
Primary Mast cells (MCs) were isolated from tumor and non-tumor regions of fresh prostate tissue obtained from a cohort of five men undergoing radical prostatectomy for localized prostate cancer (Figure S1a)
We demonstrate that SAMD14 alters the secreted profile of MCs to promote the normalization of extracellular matrix (ECM) matrix deposited by prostatic Cancer-associated fibroblasts (CAFs)

Summary

Introduction

Prostate cancer is the second most commonly diagnosed male cancer worldwide, and the fifth leading cause of cancer death in men [1]. Following malignant transformation, prostate cancer cells invade the surrounding stroma, activating the tumor microenvironment (TME) [4]. It is established that the prostate TME contributes to tumor initiation and disease progression [5,6,7], the reciprocal and heterotypic cellular interactions that occur within the tumor stroma remain less well-defined. Cancer-associated fibroblasts (CAFs) are present in the early stages of tumorigenesis and differ from their non-malignant prostate fibroblast (NPF) counterparts at the transcriptomic [8], epigenomic [9,10], and proteomic level [11]. The reciprocal interactions between CAFs and immune cells modulate the biochemical and physiological structure of the TME to promote or suppress tumor growth [17]

Methods

Results

Discussion

Conclusion