Know Thy Model: Charting Molecular Homology in Stromal Reprogramming Between Canine and Human Mammary Tumors.

Enni Markkanen

doi:10.3389/fcell.2019.00348

Abstract

Spontaneous canine simple mammary tumors (CMTs) are often viewed as models of human breast cancer. Cancer-associated stroma (CAS) is central for initiation and progression of human cancer, and is likely to play a key role in canine tumors as well. Until recently, however, canine CAS in general, and in CMT in particular, lacked detailed characterization and it remained unclear how canine and human CAS compare. This void in knowledge regarding canine CAS and the resulting lack of unbiased cross-species analysis of molecular homologies and differences undermined the validity of the canine model for human disease. To assess stromal reprogramming in canine breast tumors, we have recently established a protocol to specifically isolate and analyze CAS and matched normal stroma from archival, formalin-fixed paraffin embedded (FFPE) clinical tumor samples using laser-capture microdissection followed by next-generation RNA-sequencing. Using this approach, we have analyzed stromal reprogramming in both malignant canine mammary carcinomas (mCAs) as well as benign canine mammary adenomas in a series of studies. Our results demonstrate strong stromal reprogramming in CMTs and identify high-grade molecular homology between human and canine CAS. Here, I aim to give a short background on the value of comparative oncology in general, and spontaneous CMT in particular. This will be followed by a concise review of the current knowledge of stromal reprogramming in both malignant canine mCA and benign adenoma. Finally, I will conclude with insights on highly conserved aspects of stromal reprogramming between CMT and human breast cancer that accentuate the relevance of CAS in CMT as a model for the human disease.

Highlights

The majority of all cancers derive from corrupted epithelial cells that give rise to tumor cells that disregard the tissue boundaries of their natural habitat
MRNA levels that mirror closely results obtained on protein level, with increasing abundance from normal stroma to adenoma to carcinoma; (ii) a number of targets whose expression has been positively correlated with increasing malignancy show no changes in stromal mRNA abundance between the three entities; (iii) there are some genes whose expression is opposite of what would be expected from literature regarding protein levels (e.g., MMP2, MMP13, TIMP3, and VEGFR2); and (iv) one of the advantages of RNAseq-based analysis is differentiation between closely related isoforms, e.g., changes in vascular endothelial growth factors (VEGFs) that are very specific to the different isoforms of the protein
We demonstrated that the high level of molecular homology between canine and human stromal reprogramming manifested in a prognostic value of the canine Cancer-associated stroma (CAS) signature, with upregulated genes in canine CAS highly enriched among adversely prognostic genes in humans, and upregulated genes in canine normal stroma highly enriched among favorably prognostic genes in humans

Summary

Introduction

The majority of all cancers derive from corrupted epithelial cells that give rise to tumor cells that disregard the tissue boundaries of their natural habitat. Recent work by my group has begun to assess stromal reprogramming in spontaneous CMTs by next-generation RNA-sequencing (RNAseq) in both malignant canine mammary carcinomas (mCAs) and benign canine mammary adenomas, and to probe the extent of molecular homology between human and canine CAS.

Results

Conclusion