Differential stromal reprogramming in benign and malignant naturally occurring canine mammary tumours identifies disease-modulating stromal components

Parisa Amini,Sina Nassiri,Alexandra Malbon,Enni Markkanen

doi:10.1038/s41598-020-62354-8

Parisa Amini, Sina Nassiri + Show 2 more

Open Access

https://doi.org/10.1038/s41598-020-62354-8

Copy DOI

Abstract

While cancer-associated stroma (CAS) in malignant tumours is well described, stromal changes in benign forms of naturally occurring tumours remain poorly characterized. Spontaneous canine mammary carcinomas (mCA) are viewed as excellent models of human mCA. We have recently reported highly conserved stromal reprogramming between canine and human mCA based on transcriptome analysis of laser-capture-microdissected FFPE specimen. To identify stromal changes between benign and malignant mammary tumours, we have analysed matched normal and adenoma-associated stroma (AAS) from 13 canine mammary adenomas and compared them to previous data from 15 canine mCA. Our analyses reveal distinct stromal reprogramming even in small benign tumours. While similarities between AAS and CAS exist, the stromal signature clearly distinguished adenomas from mCA. The distinction between AAS and CAS is further substantiated by differential enrichment in several hallmark signalling pathways as well as differential abundance in cellular composition. Finally, we identify COL11A1, VIT, CD74, HLA-DRA, STRA6, IGFBP4, PIGR, and TNIP1 as strongly discriminatory stromal genes between adenoma and mCA, and demonstrate their prognostic value for human breast cancer. Given the relevance of canine CAS as a model for the human disease, our approach identifies disease-modulating stromal components with implications for both human and canine breast cancer.

Highlights

While cancer-associated stroma (CAS) in malignant tumours is well described, stromal changes in benign forms of naturally occurring tumours remain poorly characterized
To understand stromal reprogramming in canine mammary carcinomas (mCA) and how it compares to human mCA, we have previously analysed CAS reprogramming in formalin-fixed paraffin embedded (FFPE) breast cancer tissue using by laser-capture-microdissection (LCM) and quantitative PCR (RT-qPCR), and further advanced the approach to analyse LCM subsections by next-generation sequencing (RNAseq)[10,11]
Using this powerful RNAseq-driven approach, we have very recently assessed stromal reprogramming in a set of 15 canine mCA, and demonstrated strong molecular homology in stromal reprogramming between canine and human mCA, emphasizing the relevance of the canine model for the human disease with regards to CAS reprogramming[12]

Summary

Introduction

While cancer-associated stroma (CAS) in malignant tumours is well described, stromal changes in benign forms of naturally occurring tumours remain poorly characterized. Canine simple mammary adenomas are well-demarcated, non-infiltrative benign mammary tumours generally associated with little fibrovascular supporting stroma[9] Whether these benign adenomas can progress into more malignant forms, such as mCA, remains an unresolved controversy. To understand stromal reprogramming in canine mCA and how it compares to human mCA, we have previously analysed CAS reprogramming in formalin-fixed paraffin embedded (FFPE) breast cancer tissue using by laser-capture-microdissection (LCM) and quantitative PCR (RT-qPCR), and further advanced the approach to analyse LCM subsections by next-generation sequencing (RNAseq)[10,11]. Using this powerful RNAseq-driven approach, we have very recently assessed stromal reprogramming in a set of 15 canine mCA, and demonstrated strong molecular homology in stromal reprogramming between canine and human mCA, emphasizing the relevance of the canine model for the human disease with regards to CAS reprogramming[12]

Objectives

Methods

Results

Conclusion