Multi-omics characterization of lymphedema-induced adipose tissue from breast cancer patients

Objective Secondary lymphedema (LE) following breast cancer surgery is a life-long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to the surgery-induced LE in short- and long-term LE patients, and compared the transcriptomic landscape in LE to the obesity-induced adipose tissue. Methods Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n=20 patients). To decipher molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Results Integrative analysis of functional genomics revealed that inflammatory response, cell chemotaxis and angiogenesis were upregulated biological processes in the LE arm, indicating a sustained inflammation in the edematous adipose tissue, whereas, epidermal differentiation, cell-cell junction organization, water homeostasis and neurogenesis were, in turn, downregulated in the LE arm. Surprisingly, only few genes were found to be the same in the LE-induced and the obesity-induced adipose tissue expansion, indicating a different type of adipose tissue development in these two diseases. In metabolomics analysis, the concentration of a branched-chain amino acid valine was found to be reduced in the edematous arm together with downregulation of mRNA levels of its transporter SLC6A15 . Lipidomics analyses did not show any significant differences between the diseased and healthy arm, suggesting that diet affects the lipid composition of the adipose tissue more than the LE. Conclusions Our results provide a detailed molecular characterization of adipose tissue in secondary LE of breast cancer patients vs individuals with obesity. The results show distinct differences in transcriptomic signatures between LE patients vs individuals with obesity, but only minor differences in metabolome and lipidome between the diseased and the healthy arm. ### Competing Interest Statement The authors have declared no competing interest.