Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Sci Rep. 2020 Mar 26;10(1):5506. doi: 10.1038/s41598-020-62354-8.
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.
虽然恶性肿瘤中的癌症相关基质（cancer-associated stroma，CAS）已得到充分描述，但自然发生的良性肿瘤中的基质变化仍特征描述不足。自发性犬乳腺肿瘤（canine mammary carcinomas，mCA）被认为是人类 mCA 的极佳模型。我们最近基于对激光捕获微切割 FFPE 标本的转录组分析，报道了犬和人 mCA 之间高度保守的基质重编程。为了鉴定良性和恶性乳腺肿瘤之间的基质变化，我们分析了 13 个犬乳腺腺瘤中的匹配正常和腺瘤相关基质（adenoma-associated stroma，AAS），并将其与之前 15 个犬 mCA 的数据进行了比较。我们的分析揭示了即使在小的良性肿瘤中也存在明显的基质重编程。尽管 AAS 和 CAS 之间存在相似之处，但基质特征可明确区分腺瘤和 mCA。AAS 和 CAS 之间的区别还通过几个标志性信号通路的差异富集以及细胞组成的差异丰度得到进一步证实。最后，我们确定 COL11A1、VIT、CD74、HLA-DRA、STRA6、IGFBP4、PIGR 和 TNIP1 是区分腺瘤和 mCA 的强烈鉴别性基质基因，并证明它们对人类乳腺癌具有预后价值。鉴于犬类 CAS 作为人类疾病模型的相关性，我们的方法确定了具有人类和犬类乳腺癌意义的疾病调节性基质成分。
