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Adipose-enriched peri-tumoral stroma, in contrast to myofibroblast-enriched stroma, prognosticates poorer survival in breast cancers.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211729 | GEO | 2022/08/22

REPOSITORIES: GEO

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Project description:Background: Vulvar squamous cell carcinoma (vSCC) is a rare but debilitating disease. One vSCC subtype comprises tumor cells that grow and expand as a cohesive sheet of cells that “pushes” and compresses the associated lymphoplasmacytic (LPC) stroma. Another vSCC subtype features tumor cells that grow in loose association with other tumor cells and infiltrate the associated fibromyxoid (FMX) stroma consisting mainly of extracellular matrix. Clinically, infiltrative vSCC with FMX stroma (Inf/FMX) is significantly associated with lymph node metastases and recurrence. Methods: An unbiased proteomic approach was used to identify pathways that could produce these different vSCC subtypes. Formalin-fixed and paraffin-embedded tissues from 10 cases of pushing vSCC with LPC stroma (Push/LPC) and 8 cases of Inf/FMX were subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Analysis identified 2,265 different proteins in the 18 samples of vSCC. Of these, 344 proteins were differentially expressed (p<0.05) by at least 4-fold between vSCC subtypes. Of these, 59 were higher and 285 lower in Inf/FMX compared to Push/LPC tumors. Consistent with the desmoplastic morphology and increased picrosirius red staining, expression of subunits of several collagens (Col 1, 3, 6, 14, 18) was higher in the more aggressive Inf/FMX tumors. In contrast, signal transducer and activator of transcription 1 (STAT1), an important regulator of several inflammatory pathways, was expressed at lower levels in the Inf/FMX tumors. This finding was confirmed by immunohistochemistry using an antibody to STAT1. An informatics analysis of the differing profiles identified differences in the integrin signaling pathway and inflammation mediated by chemokine and cytokine signaling pathway. This analysis also linked decreased expression of proteins involved antigen processing and presentation and increased expression of those with cell-matrix adhesion as processes with the more aggressive Inf/FMX vSCC subtype. Conclusions: Comparing the proteomic profiles of vSCC morphologic subtypes indicates that increased expression of collagen subunits and decreased expression of STAT1 are associated with a more aggressive tumor subtype. Informatic analyses further identify alterations in cell interaction with matrix and immune function differ with tumor aggressiveness. Identification of these pathways provides a molecular basis for understanding aggressiveness of vSCC.

Project description:Breast cancer is an extremely heterogeneous disease. This heterogeneity can be observed at multiple levels, including gene expression, chromosomal aberrations, and disease pathology. A clear understanding of these differences is important since they impact upon treatment efficacy and clinical outcome. Many studies have shown that the tumor microenvironment also plays a critical role in cancer initiation and progression. Although genomic technologies have been used to gain a better understanding of the impact of gene expression heterogeneity on breast cancer outcome by identifying gene expression signatures associated with clinical outcome, histopathological breast cancer subtypes, and a variety of cancer--related pathways and processes, relatively little is known about the influence of of heterogeneity in the tumor microenvironment on these factors. We show that gene expression in the breast tumor microenvironment is highly heterogeneous, identifying at least six different classes of tumor stroma with distinct expression patterns and distinct biological processes. Two of these classes recapitulate the processes identified in the stroma--derived prognostic predictor, while the others are new classes of stroma associated with distinct clinical outcomes. One of these is associated with matrix remodeling and is strongly associated with the basal molecular subtype of breast cancer. The remainder are independent of the previously published molecular subtypes of breast cancer. Additionally, based on independent data from over 800 tumors, the combinations of stroma classes and breast cancer subtypes identify new subgroups of breast tumors that show better discrimination between good and poor outcome individuals than the molecular breast cancer subtypes or the stroma classes alone, suggesting a novel classification scheme for breast cancer . This further demonstrates an important role for the tumor microenvironment in defining breast cancer heterogeneity, with a consequent impact upon clinical outcome.

Project description:The diversity of cell-cell interactions in different regions of a tumor reflects the functional heterogeneity of cancer, which poses challenges in early diagnosis, selection of treatment strategies, and prognosis of breast cancer. Cancer cells interact with each other to form different morphological structures in the tumor and stromal host cells via integrins. The objective of this study was to characterize the morphological and spatial heterogeneity of primary breast tumors in the context of expression profiles of integrins and their ligands. We studied spatial transcriptomics using the 10X Visium approach and the NICHES algorithm to map ligand-receptor signaling pathways and visualize the heterogeneity of signaling archetypes in tumor clusters. Cluster analysis of the expression profiles of tumor spots from the samples indicated pronounced inter-tumoral heterogeneity. Integrin-ligand functional clusters were associated with intratumoral heterogeneity, which was manifested by the presence of several morphological loci as observed in histological tumor samples. Inter-tumoral heterogeneity was manifested by a different number of functional clusters, ranging from 2 to 9 for each tumor sample. The main characteristic of these clusters was the significant predominance of non-complementary integrin subunits. Of the 42 functional integrin-ligand pairs in 21 clusters of five samples, 41 pairs occurred only once. The exception was the LAMA5-ITGB4 pair, which was detected in two clusters of different samples. The spatial heterogeneity of integrin-ligand expression clusters in breast cancer contributes significantly to the functional heterogeneity of the tumor, which sets the stage for many scenarios of parenchymatous-stromal relationships, some of which may be effective in the emergence of metastasizing tumor seed cells. The intra- and inter-tumoral spatio-functional heterogeneity of the tumor tissue that we discovered may largely explain why it is difficult to achieve success in most patients with breast cancer using any therapeutic strategy targeting one molecule of the vast array, regardless of the importance of its pathogenetic significance.

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Adipose-enriched peri-tumoral stroma, in contrast to myofibroblast-enriched stroma, prognosticates poorer survival in breast cancers.

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