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Molecular and epigenetic ex vivo profiling of testis cancer-associated fibroblasts and their interaction with germ cell tumor cells and macrophages.
- Source :
-
Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2024 Sep; Vol. 132, pp. 10-23. Date of Electronic Publication: 2024 Jun 06. - Publication Year :
- 2024
-
Abstract
- Germ cell tumors (GCT) are the most common solid tumors in young men of age 15 - 40. In previous studies, we profiled the interaction of GCT cells with cells of the tumor microenvironment (TM), which showed that especially the 3D interaction of fibroblasts (FB) or macrophages with GCT cells influenced the growth behavior and cisplatin response as well as the transcriptome and secretome of the tumor cells, suggesting that the crosstalk of these cells with GCT cells is crucial for tumor progression and therapy outcome. In this study, we shed light on the mechanisms of activation of cancer-associated fibroblasts (CAF) in the GCT setting and their effects on GCT cells lines and the monocyte cell line THP-1. Ex vivo cultures of GCT-derived CAF were established and characterized molecularly and epigenetically by performing DNA methylation arrays, RNA sequencing, and mass spectrometry-based secretome analysis. We demonstrated that the activation state of CAF is influenced by their former prevailing tumor environment in which they have resided. Hereby, we postulate that seminoma (SE) and embryonal carcinoma (EC) activate CAF, while teratoma (TER) play only a minor role in CAF formation. In turn, CAF influence proliferation and the expression of cisplatin sensitivity-related factors in GCT cells lines as well as polarization of in vitro-induced macrophages by the identified effector molecules IGFBP1, LGALS3BP, LYVE1, and PTX3. Our data suggests that the vital interaction of CAF with GCT cells and with macrophages has a huge influence on shaping the extracellular matrix as well as on recruitment of immune cells to the TM. In conclusion, therapeutically interfering with CAF and / or macrophages in addition to the standard therapy might slow-down progression of GCT and re-shaping of the TM to a tumor-promoting environment. Significance: The interaction of CAF with GCT and macrophages considerably influences the microenvironment. Thus, therapeutically interfering with CAF might slow-down progression of GCT and re-shaping of the microenvironment to a tumor-promoting environment.<br />Competing Interests: Conflict of interest statement All authors declare to have no conflict of interest<br /> (Copyright © 2024. Published by Elsevier B.V.)
- Subjects :
- Male
Humans
Gene Expression Regulation, Neoplastic
DNA Methylation
Cell Line, Tumor
Cell Communication
Cisplatin pharmacology
THP-1 Cells
Cell Proliferation
Testicular Neoplasms metabolism
Testicular Neoplasms genetics
Testicular Neoplasms pathology
Tumor Microenvironment
Cancer-Associated Fibroblasts metabolism
Cancer-Associated Fibroblasts pathology
Neoplasms, Germ Cell and Embryonal genetics
Neoplasms, Germ Cell and Embryonal metabolism
Neoplasms, Germ Cell and Embryonal pathology
Macrophages metabolism
Macrophages pathology
Epigenesis, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1569-1802
- Volume :
- 132
- Database :
- MEDLINE
- Journal :
- Matrix biology : journal of the International Society for Matrix Biology
- Publication Type :
- Academic Journal
- Accession number :
- 38851302
- Full Text :
- https://doi.org/10.1016/j.matbio.2024.06.001