Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer

Robson Francisco Carvalho; Luisa Matos do Canto; Cecilie Abildgaard; Mads Malik Aagaard; Monica Søgaard Tronhjem; Marianne Waldstrøm; Lars Henrik Jensen; Karina Dahl Steffensen; Silvia Regina Rogatto

doi:10.1186/s12964-022-00991-4

Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer

Robson Francisco Carvalho^*, Luisa Matos do Canto, Cecilie Abildgaard, Mads Malik Aagaard, Monica Søgaard Tronhjem, Marianne Waldstrøm, Lars Henrik Jensen, Karina Dahl Steffensen, Silvia Regina Rogatto

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

Background: Serous ovarian carcinoma is the most frequent histological subgroup of ovarian cancer and the leading cause of death among gynecologic tumors. The tumor microenvironment and cancer-associated fibroblasts (CAFs) have a critical role in the origin and progression of cancer. We comprehensively characterized the crosstalk between CAFs and ovarian cancer cells from malignant fluids to identify specific ligands and receptors mediating intercellular communications and disrupted pathways related to prognosis and therapy response. Methods: Malignant fluids of serous ovarian cancer, including tumor-derived organoids, CAFs-enriched (eCAFs), and malignant effusion cells (no cultured) paired with normal ovarian tissues, were explored by RNA-sequencing. These data were integrated with single-cell RNA-sequencing data of ascites from ovarian cancer patients. The most relevant ligand and receptor interactions were used to identify differentially expressed genes with prognostic values in ovarian cancer. Results: CAF ligands and epithelial cancer cell receptors were enriched for PI3K-AKT, focal adhesion, and epithelial-mesenchymal transition signaling pathways. Collagens, MIF, MDK, APP, and laminin were detected as the most significant signaling, and the top ligand-receptor interactions THBS2/THBS3 (CAFs)—CD47 (cancer cells), MDK (CAFs)—NCL/SDC2/SDC4 (cancer cells) as potential therapeutic targets. Interestingly, 34 genes encoding receptors and ligands of the PI3K pathway were associated with the outcome, response to treatment, and overall survival in ovarian cancer. Up-regulated genes from this list consistently predicted a worse overall survival (hazard ratio > 1.0 and log-rank P < 0.05) in two independent validation cohorts. Conclusions: This study describes critical signaling pathways, ligands, and receptors involved in the communication between CAFs and cancer cells that have prognostic and therapeutic significance in ovarian cancer. [MediaObject not available: see fulltext.].

Originalsprog	Engelsk
Artikelnummer	176
Tidsskrift	Cell Communication and Signaling
Vol/bind	20
Antal sider	19
ISSN	1478-811X
DOI	https://doi.org/10.1186/s12964-022-00991-4
Status	Udgivet - dec. 2022

Bibliografisk note

Funding Information:
The results shown here are in part based upon data generated by the Genotype-Tissue Expression project (GTEx) ( https://gtexportal.org/ ) and by the TCGA Research Network ( http://cancergenome.nih.gov/ ). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Funding Information:
This study was supported by grants from the Region of Southern Denmark Research Fund (J.nr.: 20/14277, Efond 519), Denmark. The study was developed in collaboration with the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES), in the scope of the Program CAPES-PrInt (process number 88887.310463/2018–00).

Dokumenter og links

10.1186/s12964-022-00991-4Licens: CC BY

Open Access VersionForlagets udgivne version, 9,66 MBLicens: CC BY

SDU link

Tjek adgangen til materialet i Syddansk Universitetsbiblioteks søgemaskine

Citationsformater

Carvalho, R. F., do Canto, L. M., Abildgaard, C., Aagaard, M. M., Tronhjem, M. S., Waldstrøm, M., Jensen, L. H., Steffensen, K. D., & Rogatto, S. R. (2022). Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer. Cell Communication and Signaling, 20, Artikel 176. https://doi.org/10.1186/s12964-022-00991-4

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title = "Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer",

abstract = "Background: Serous ovarian carcinoma is the most frequent histological subgroup of ovarian cancer and the leading cause of death among gynecologic tumors. The tumor microenvironment and cancer-associated fibroblasts (CAFs) have a critical role in the origin and progression of cancer. We comprehensively characterized the crosstalk between CAFs and ovarian cancer cells from malignant fluids to identify specific ligands and receptors mediating intercellular communications and disrupted pathways related to prognosis and therapy response. Methods: Malignant fluids of serous ovarian cancer, including tumor-derived organoids, CAFs-enriched (eCAFs), and malignant effusion cells (no cultured) paired with normal ovarian tissues, were explored by RNA-sequencing. These data were integrated with single-cell RNA-sequencing data of ascites from ovarian cancer patients. The most relevant ligand and receptor interactions were used to identify differentially expressed genes with prognostic values in ovarian cancer. Results: CAF ligands and epithelial cancer cell receptors were enriched for PI3K-AKT, focal adhesion, and epithelial-mesenchymal transition signaling pathways. Collagens, MIF, MDK, APP, and laminin were detected as the most significant signaling, and the top ligand-receptor interactions THBS2/THBS3 (CAFs)—CD47 (cancer cells), MDK (CAFs)—NCL/SDC2/SDC4 (cancer cells) as potential therapeutic targets. Interestingly, 34 genes encoding receptors and ligands of the PI3K pathway were associated with the outcome, response to treatment, and overall survival in ovarian cancer. Up-regulated genes from this list consistently predicted a worse overall survival (hazard ratio > 1.0 and log-rank P < 0.05) in two independent validation cohorts. Conclusions: This study describes critical signaling pathways, ligands, and receptors involved in the communication between CAFs and cancer cells that have prognostic and therapeutic significance in ovarian cancer. [MediaObject not available: see fulltext.].",

keywords = "Cancer-associated fibroblasts, Cell–cell communication, Organoids, Serous ovarian cancer, Single-cell RNA-sequencing, Humans, Phosphatidylinositol 3-Kinases/metabolism, RNA/metabolism, Sequence Analysis, RNA, Fibroblasts/metabolism, Cell Line, Tumor, Female, Ligands, Tumor Microenvironment/genetics, Ovarian Neoplasms/pathology",

author = "Carvalho, {Robson Francisco} and {do Canto}, {Luisa Matos} and Cecilie Abildgaard and Aagaard, {Mads Malik} and Tronhjem, {Monica S{\o}gaard} and Marianne Waldstr{\o}m and Jensen, {Lars Henrik} and Steffensen, {Karina Dahl} and Rogatto, {Silvia Regina}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s12964-022-00991-4",

language = "English",

volume = "20",

journal = "Cell Communication and Signaling",

issn = "1478-811X",

publisher = "BioMed Central",

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TY - JOUR

T1 - Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer

AU - Carvalho, Robson Francisco

AU - do Canto, Luisa Matos

AU - Abildgaard, Cecilie

AU - Aagaard, Mads Malik

AU - Tronhjem, Monica Søgaard

AU - Waldstrøm, Marianne

AU - Jensen, Lars Henrik

AU - Steffensen, Karina Dahl

AU - Rogatto, Silvia Regina

PY - 2022/12

Y1 - 2022/12

N2 - Background: Serous ovarian carcinoma is the most frequent histological subgroup of ovarian cancer and the leading cause of death among gynecologic tumors. The tumor microenvironment and cancer-associated fibroblasts (CAFs) have a critical role in the origin and progression of cancer. We comprehensively characterized the crosstalk between CAFs and ovarian cancer cells from malignant fluids to identify specific ligands and receptors mediating intercellular communications and disrupted pathways related to prognosis and therapy response. Methods: Malignant fluids of serous ovarian cancer, including tumor-derived organoids, CAFs-enriched (eCAFs), and malignant effusion cells (no cultured) paired with normal ovarian tissues, were explored by RNA-sequencing. These data were integrated with single-cell RNA-sequencing data of ascites from ovarian cancer patients. The most relevant ligand and receptor interactions were used to identify differentially expressed genes with prognostic values in ovarian cancer. Results: CAF ligands and epithelial cancer cell receptors were enriched for PI3K-AKT, focal adhesion, and epithelial-mesenchymal transition signaling pathways. Collagens, MIF, MDK, APP, and laminin were detected as the most significant signaling, and the top ligand-receptor interactions THBS2/THBS3 (CAFs)—CD47 (cancer cells), MDK (CAFs)—NCL/SDC2/SDC4 (cancer cells) as potential therapeutic targets. Interestingly, 34 genes encoding receptors and ligands of the PI3K pathway were associated with the outcome, response to treatment, and overall survival in ovarian cancer. Up-regulated genes from this list consistently predicted a worse overall survival (hazard ratio > 1.0 and log-rank P < 0.05) in two independent validation cohorts. Conclusions: This study describes critical signaling pathways, ligands, and receptors involved in the communication between CAFs and cancer cells that have prognostic and therapeutic significance in ovarian cancer. [MediaObject not available: see fulltext.].

AB - Background: Serous ovarian carcinoma is the most frequent histological subgroup of ovarian cancer and the leading cause of death among gynecologic tumors. The tumor microenvironment and cancer-associated fibroblasts (CAFs) have a critical role in the origin and progression of cancer. We comprehensively characterized the crosstalk between CAFs and ovarian cancer cells from malignant fluids to identify specific ligands and receptors mediating intercellular communications and disrupted pathways related to prognosis and therapy response. Methods: Malignant fluids of serous ovarian cancer, including tumor-derived organoids, CAFs-enriched (eCAFs), and malignant effusion cells (no cultured) paired with normal ovarian tissues, were explored by RNA-sequencing. These data were integrated with single-cell RNA-sequencing data of ascites from ovarian cancer patients. The most relevant ligand and receptor interactions were used to identify differentially expressed genes with prognostic values in ovarian cancer. Results: CAF ligands and epithelial cancer cell receptors were enriched for PI3K-AKT, focal adhesion, and epithelial-mesenchymal transition signaling pathways. Collagens, MIF, MDK, APP, and laminin were detected as the most significant signaling, and the top ligand-receptor interactions THBS2/THBS3 (CAFs)—CD47 (cancer cells), MDK (CAFs)—NCL/SDC2/SDC4 (cancer cells) as potential therapeutic targets. Interestingly, 34 genes encoding receptors and ligands of the PI3K pathway were associated with the outcome, response to treatment, and overall survival in ovarian cancer. Up-regulated genes from this list consistently predicted a worse overall survival (hazard ratio > 1.0 and log-rank P < 0.05) in two independent validation cohorts. Conclusions: This study describes critical signaling pathways, ligands, and receptors involved in the communication between CAFs and cancer cells that have prognostic and therapeutic significance in ovarian cancer. [MediaObject not available: see fulltext.].

KW - Cancer-associated fibroblasts

KW - Cell–cell communication

KW - Organoids

KW - Serous ovarian cancer

KW - Single-cell RNA-sequencing

KW - Humans

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - RNA/metabolism

KW - Sequence Analysis, RNA

KW - Fibroblasts/metabolism

KW - Cell Line, Tumor

KW - Female

KW - Ligands

KW - Tumor Microenvironment/genetics

KW - Ovarian Neoplasms/pathology

U2 - 10.1186/s12964-022-00991-4

DO - 10.1186/s12964-022-00991-4

M3 - Journal article

C2 - 36352420

AN - SCOPUS:85141464842

SN - 1478-811X

VL - 20

JO - Cell Communication and Signaling

JF - Cell Communication and Signaling

M1 - 176

ER -

Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer

Abstract

Bibliografisk note

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