Adipose-enriched peri-tumoral stroma, in contrast to myofibroblast-enriched stroma, prognosticates poorer survival in breast cancers.
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ABSTRACT:
PROVIDER: PRJNA871907 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancers display a high degree of diversity between and within tumors due to variations in both tumor cells and non-malignant cells of the tumor microenvironment (TME). While most studies on the TME have focused on stroma located within the tumor mass, few studies have examined the peri-tumoral microenvironment, which extends beyond the tumor margins and includes the surrounding, benign-appearing tissues. Here, we examined the heterogeneity in tumors and peri-tumoral stroma from 10 ER+PR+HER2- invasive breast carcinomas, through multi-region transcriptomic profiling. Tumor samples were obtained from the center, superior, inferior, medial, and lateral (C, S, Inf, M, L) regions of each tumor. Peritumoral samples were obtained from four radial directions corresponding to the regions the tumor samples were collected from (S, Inf, M, L) and from three zones of increasing distances from the tumor margins (Zone 1: 1-3 cm, Zone 2: 3-5 cm, Zone 3: 5-7 cm). To represent the normal breast transcriptomic state, 5 non-directional samples were each obtained from 3 non-tumor bearing breasts (NTB) - 1 patient had undergone cosmetic reduction mammoplasty and 2 patients were germline BRCA2-mutation carriers who had undergone risk-reducing mammoplasties. Total RNA was isolated and microarray was performed using the human Clariom™ S Assay (ThermoFisher Scientific). In total, 144 transcriptomic profiles (47 Tumor, 82 peri-tumoral stroma, 15 NTB) were analyzed. Heterogeneity was observed both within and between the tumor samples, highlighting that unlike the histological classification, an individual tumor is often comprised of several molecular sub-types. Similarly, the peri-tumoral stroma was also heterogeneous, albeit independent of the tumor heterogeneity. Four distinct stromal clusters were noted, which differed in their molecular pathways and cell type composition. Among these, the adipose-enriched stroma that had inflammatory cancer-associated fibroblasts and innate immune cells was significantly associated with poorer overall survival, in contrast to the myofibroblast-enriched stroma. These data together suggest that the peri-tumoral heterogeneity may be an important determinant of the evolution and treatment of breast cancers.
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Project description:Despite our understanding of the genetic basis of intra-tumoral heterogeneity, the role of stromal heterogeneity arising from an altered tumor microenvironment in affecting tumorigenesis is poorly understood. In particular, extensive study on the peri-tumoral stroma in the morphologically normal tissues surrounding the tumor is lacking. Here, we examine the heterogeneity in tumors and peri-tumoral stroma from 8 ER+/PR+/HER2- invasive breast carcinomas, through multi-region transcriptomic profiling by microarray. We describe the regional heterogeneity observed at the intrinsic molecular subtype, pathway enrichment, and cell type composition levels within each tumor and its peri-tumoral region, up to 7 cm from the tumor margins. Moreover, we identify a pro-inflammatory adipose-enriched peri-tumoral subtype which was significantly associated with poorer overall survival in breast cancer patients, in contrast to an adaptive immune cell- and myofibroblast-enriched subtype. These data together suggest that peri-tumoral heterogeneity may be an important determinant of the evolution and treatment of breast cancers.
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