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

Cheryl Cero ^1,2, John S House ³, Vincenzo Verdi ¹

¹Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
²Division of Cancer Biology, Cancer Cell Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA.
⁴State Laboratory of Public Health, North Carolina Department of Health and Human Services, Raleigh, NC, USA.
⁵Center of Human Health and the Environment and Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
⁶Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
⁷StageBio, Frederick, MD, USA.
⁸Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
⁹Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. heather.shive@nih.gov.
¹⁰Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA. heather.shive@nih.gov.

⁰Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Oncogene +

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November 7, 2024

View abstract on PubMed

Summary

Researchers developed a zebrafish model to study soft tissue sarcoma (STS) development. This model reveals how the tumor microenvironment influences malignant peripheral nerve sheath tumor (MPNST) progression and identifies potential therapeutic targets.

Area Of Science

Oncology
Developmental Biology
Genomics

Background

The role of the microenvironment in soft tissue sarcoma (STS) progression, especially during tumor initiation, remains unclear.
Existing animal models face challenges in distinguishing between microenvironmental, precancerous, and cancer cells, hindering research into the precancerous microenvironment.

Purpose Of The Study

To develop a novel zebrafish model for dissecting microenvironmental contributions to STS development.
To identify key molecular mechanisms and cellular players involved in the transition from precancerous lesions to malignant peripheral nerve sheath tumors (MPNST).

Main Methods

Development of a zebrafish model enabling cell population segregation via fluorescence-activated cell sorting.
Transcriptomic profiling (RNA-seq) of microenvironmental, precancerous, and cancer cells.
Comparative genomics analysis of human and zebrafish MPNST and benign lesions.
Functional validation of candidate genes in human MPNST.

Main Results

Broad activation of inflammation and immune-associated signaling networks was observed.
Distinct gene expression patterns were identified during the transition from precancerous to cancer microenvironments.
Macrophages were identified as potential contributors to microenvironmental phenotypes.
Conserved gene expression changes and candidate genes were identified through comparative genomics.
Periostin (POSTN), an extracellular matrix protein, was functionally validated in human MPNST.

Conclusions

The zebrafish model provides a powerful tool for studying STS initiation and progression.
The tumor microenvironment plays a significant role in regulating MPNST development.
Periostin (POSTN) emerges as a potential therapeutic target for MPNST.