Profiling the cancer-prone microenvironment in a zebrafish model for MPNST.

Abstract

Microenvironmental contributions to soft tissue sarcoma progression are relatively undefined, particularly during sarcoma onset. Use of animal models to reveal these contributions is impeded by difficulties in discriminating between microenvironmental, precancerous, and cancer cells, and challenges in defining a precancerous microenvironment. We developed a zebrafish model that allows segregation of microenvironmental, precancerous, and cancerous cell populations by fluorescence-activated cell sorting. This model has high predilection for malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma that exhibits rapid, aggressive growth. Using RNA-seq, we profiled the transcriptomes of microenvironmental, precancerous, and cancer cells from our zebrafish MPNST model. We show broad activation of inflammation/immune-associated signaling networks, describe gene expression patterns that uniquely characterize the transition from precancerous to cancer ME, and identify macrophages as potential contributors to microenvironmental phenotypes. We identify conserved gene expression changes and candidate genes of interest by comparative genomics analysis of MPNST versus benign lesions in both humans and zebrafish. Finally, we functionally validate a candidate extracellular matrix protein, periostin (POSTN), in human MPNST. This work provides insight into how the microenvironment may regulate MPNST initiation and progression.