Abstract 6838: Adipose tissue features in breast cancer patients: Impact and modifications induced by tumor according to body mass index

Abstract

Abstract Adipose tissue (AT) is emerging as a contributing factor to cancer development and progression, especially in obesity. However, the mechanisms underlying this association are not yet fully understood. Based on the described in vitro interplay between cancer cells and adipocytes that induces adipocyte dedifferentiation and the acquisition of an inflammatory phenotype, it is conceivable that tumor-adipocyte crosstalk promotes cancer progression even in normal weight patients (pts). To study tumor-induced AT alterations, we performed a transcriptomic analysis of matched adjacent and distant tumor AT samples from 41 breast cancer (BC) pts (78% Luminal B, 12% HER2+, 7% TNBC) undergoing mastectomy. Comparison of the gene expression landscape of BC-adjacent vs distant ATs derived from normal weight pts (BMI<25, n=28) identified 723 differentially expressed genes (FDR<10%). Metabolic signaling processes were over-represented in genes resulted downmodulated in the BC-adjacent AT, while those upmodulated were mainly classified into proliferation, migration and inflammatory response, cell programs associated with dedifferentiated adipocytes in vitro. Accordingly, BC-adjacent ATs were found to be enriched (NES=1.78, p<0.0001) in a set of genes unique of in vitro dedifferentiated adipocytes compared to mature adipocytes. In overweight/obese pts, no differentially expressed genes were found between BC-adjacent and -distant ATs, although gene sets composed of modulated genes in normal weight pts were found to be significantly enriched (NES=1.50, p<0.0001; NES=-1.52, p=0.0025). In addition, a significant enrichment of altered BC-adjacent AT genes and inflammatory response process was observed (NES=1.49, p=0.0029; NES=1.62, p=0.011) in the BC-distal AT of overweight/obese vs normal weight pts, indicating that AT is already altered and inflamed independently of the presence of the tumor in overweight/obese women. To further analyze AT heterogeneity, we performed an unsupervised clustering of all AT samples using the K-means algorithm. Five stable clusters were identified, which were independent of sampling site. Indeed, the matched AT samples derived from 70% of the pts were assigned to the same cluster, with a significant grouping of overweight/obese pts in clusters K1 and K2 (p=0.0217). BC-adjacent AT samples from the remaining pts clustered significantly (p=0.030) in the other 3 clusters, especially in K5, which had the highest CAA score, a signature reflecting adipocyte dedifferentiation. Consistent with the association with obesity, K1/K2 pts had significantly higher circulating PCR, cholesterol, triglycerides and insulin and recurrence rate. Overall these data suggest that BC cells induce adipocyte modifications in normal weight pts and that obesity-associated BC aggressiveness is related to intrinsic characteristics of adipose tissue.(Supported by AIRC) Citation Format: Sandra Romero-Cordoba, Roberto Agresti, Viola Regondi, Giovanna Trecate, Francesca Bianchi, Lucia Sfondrini, Serenella M. Pupa, Elda Tagliabue, Tiziana Triulzi. Adipose tissue features in breast cancer patients: Impact and modifications induced by tumor according to body mass index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6838.