Location matters: spatial-dependent effects of myofibroblasts determine survival in breast cancer

While cancer-associated fibroblasts (CAFs) have been historically considered pro-tumorigenic, several studies found that myofibroblast-like CAFs (myCAFs) may have tumor-restraining properties. In our previous study (PMID: 37863888), we performed multi-regional bulk transcriptomics profiling of 8 ER+/PR+/HER2- breast tumors and matched peri-tumoral tissues. We identified an adipose-enriched peri-tumoral subtype which was significantly associated with poorer overall survival in breast cancer patients, in contrast to a myofibroblast-enriched subtype. Here, we performed single-nucleus RNA-sequencing of 2 ER+/PR+/HER2- invasive breast carcinomas and their matched peri-tumoral tissues (1-7 cm from tumor margins), as well as 1 reduction mammoplasty (RM) sample. We identified tumor-induced changes in the peri-tumoral adipocytes compared to RM adipocytes, as well as a high abundance of myCAFs in the larger tumor, whereas a distinct myofibroblast-like subpopulation was found in the peri-tumoral tissues of the smaller tumor. Together with deconvolution analyses of TCGA data and 3D co-culture experiments, we show that that myofibroblasts have both tumor-promoting or -restraining roles depending on their location within or surrounding the tumor.