Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery

Sinem Karaman; Satu Lehti; Cheng Zhang; Marja Riitta Taskinen; Reijo Käkelä; Adil Mardinoglu; Håkan Brorson; Kari Alitalo; Riikka Kivelä

doi:10.1096/fj.202400498RR

Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery

Sinem Karaman^*, Satu Lehti, Cheng Zhang, Marja Riitta Taskinen, Reijo Käkelä, Adil Mardinoglu, Håkan Brorson, Kari Alitalo^*, Riikka Kivelä^*

^*Corresponding author for this work

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Abstract

Secondary lymphedema (LE) following breast cancer-related 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 of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. 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 downregulated in the LE arm. Surprisingly, only a 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 conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.

Original language	English
Article number	e70097
Journal	Faseb Journal
Volume	38
Issue number	20
Early online date	12 Oct 2024
DOIs	https://doi.org/10.1096/fj.202400498RR
Publication status	Published - 12 Oct 2024

Keywords

Humans
Female
Breast Neoplasms/metabolism
Adipose Tissue/metabolism
Middle Aged
Lymphedema/metabolism
Obesity/metabolism
Transcriptome
Aged
Adult
Metabolomics
Lipidomics
Multiomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1096/fj.202400498RR

Multi-omics characterization of_KARAMAN_Publishedonline12October2024_GOLD_VoR (CC BY)Final published version, 5.11 MBLicence: CC BY

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title = "Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery",

abstract = "Secondary lymphedema (LE) following breast cancer-related 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 of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. 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 downregulated in the LE arm. Surprisingly, only a 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 conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.",

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author = "Sinem Karaman and Satu Lehti and Cheng Zhang and Taskinen, {Marja Riitta} and Reijo K{\"a}kel{\"a} and Adil Mardinoglu and H{\aa}kan Brorson and Kari Alitalo and Riikka Kivel{\"a}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.",

year = "2024",

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doi = "10.1096/fj.202400498RR",

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T1 - Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery

AU - Karaman, Sinem

AU - Lehti, Satu

AU - Zhang, Cheng

AU - Taskinen, Marja Riitta

AU - Käkelä, Reijo

AU - Mardinoglu, Adil

AU - Brorson, Håkan

AU - Alitalo, Kari

AU - Kivelä, Riikka

PY - 2024/10/12

Y1 - 2024/10/12

N2 - Secondary lymphedema (LE) following breast cancer-related 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 of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. 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 downregulated in the LE arm. Surprisingly, only a 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 conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.

AB - Secondary lymphedema (LE) following breast cancer-related 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 of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. 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 downregulated in the LE arm. Surprisingly, only a 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 conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.

KW - Humans

KW - Female

KW - Breast Neoplasms/metabolism

KW - Adipose Tissue/metabolism

KW - Middle Aged

KW - Lymphedema/metabolism

KW - Obesity/metabolism

KW - Transcriptome

KW - Aged

KW - Adult

KW - Metabolomics

KW - Lipidomics

KW - Multiomics

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DO - 10.1096/fj.202400498RR

M3 - Article

C2 - 39394863

SN - 0892-6638

VL - 38

JO - Faseb Journal

JF - Faseb Journal

IS - 20

M1 - e70097

ER -

Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery

Abstract

Keywords

UN SDGs

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