ErbB signalling is a potential therapeutic target for vascular lesions with fibrous component
- University of Eastern Finland, Finland
- Helsinki University Hospital, Finland
Abstract
Background: Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to high recurrence of the lesions more effective therapies are needed.
Methods: As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth.
Results: We report, for the first time, expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of VEGF-A paracrinally, and regulated EC proliferation. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts.
Conclusions: Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component.
Funding: Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, and Department of Musculosceletal and Plastic Surgery, Helsinki University Hospital.
Data availability
RNA-seq data has been submitted to NCBI Gene Expression Omnibus under accession numbers GSE130807 and GSE196311 (GEO reviewer access tokens; wbivkayaxhojdqp and mbehiikgvtmfryh, respectively).
-
Activation of Epidermal Growth Factor Receptor Pathway in Slow-Flow Vascular MalformationsNCBI Gene Expression Omnibus, GSE130807.
-
Gene expression profiling of HUVEC-s expressing PIK3CA with H1047R point mutationNCBI Gene Expression Omnibus, GSE196311.
Article and author information
Author details
Seppo Ylä-Herttuala
Johanna P Laakkonen
Funding
Academy of Finland (328835)
- Johanna P Laakkonen
ERC grant (GA670951)
- Seppo Ylä-Herttuala
ERC grant (802825)
- Minna U Kaikkonen
Sigrid Jusélius Foundation
- Seppo Ylä-Herttuala
Sigrid Jusélius Foundation
- Minna U Kaikkonen
Finnish Foundation for Cardiovascular Research
- Johanna P Laakkonen
Finnish Foundation for Cardiovascular Research
- Seppo Ylä-Herttuala
Finnish Foundation for Cardiovascular Research
- Minna U Kaikkonen
Jane and Aatos Erkko Foundation
- Minna U Kaikkonen
Department of Musculosceletal and Plastic Surgery, Helsinki University Hospital
- Pia Vuola
Academy of Finland (321535)
- Johanna P Laakkonen
Academy of Finland (353376)
- Johanna P Laakkonen
Academy of Finland (287478)
- Minna U Kaikkonen
Academy of Finland (294073)
- Minna U Kaikkonen
Ella and Georg Ehnrooth foundation
- Johanna P Laakkonen
CoE of Cardiovascular and Metabolic Disease (307402)
- Seppo Ylä-Herttuala
GeneCellNano Flagship Program (337120)
- Johanna P Laakkonen
GeneCellNano Flagship Program (337120)
- Seppo Ylä-Herttuala
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments were approved by National Experimental Animal Board of Finland (Decision No Esavi-2019-004672) and carried out in accordance with guidelines of the Finnish Act on Animal Experimentation.
Human subjects: Patient sample collection was approved by the Ethical Committee of the Helsinki University hospital, Helsinki, Finland (Decision No 127/13/03/02/2010 and No 1394/2020). Control sample collection was approved by the Research Ethics Committee of the Northern Savo Hospital District, Kuopio, Finland (Decision No 139/2015). Umbilical cord collection for HUVEC isolation was performed with approval from the Research Ethics Committee of the Northern Savo Hospital District, Kuopio, Finland (Decision No 341/2015). Informed consent, and consent to publish, was obtained from all patients included in the study.
Copyright
© 2023, Jauhiainen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 860
- views
-
- 119
- downloads
-
- 3
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
ErbB signalling is a potential therapeutic target for vascular lesions with fibrous component
eLife 12:e82543.
https://doi.org/10.7554/eLife.82543
Further reading
-
- Cell Biology
Multiple gut antimicrobial mechanisms are coordinated in space and time to efficiently fight foodborne pathogens. In Drosophila melanogaster, production of reactive oxygen species (ROS) and antimicrobial peptides (AMPs) together with intestinal cell renewal play a key role in eliminating gut microbes. A complementary mechanism would be to isolate and treat pathogenic bacteria while allowing colonization by commensals. Using real-time imaging to follow the fate of ingested bacteria, we demonstrate that while commensal Lactiplantibacillus plantarum freely circulate within the intestinal lumen, pathogenic strains such as Erwinia carotovora or Bacillus thuringiensis, are blocked in the anterior midgut where they are rapidly eliminated by antimicrobial peptides. This sequestration of pathogenic bacteria in the anterior midgut requires the Duox enzyme in enterocytes, and both TrpA1 and Dh31 in enteroendocrine cells. Supplementing larval food with hCGRP, the human homolog of Dh31, is sufficient to block the bacteria, suggesting the existence of a conserved mechanism. While the immune deficiency (IMD) pathway is essential for eliminating the trapped bacteria, it is dispensable for the blockage. Genetic manipulations impairing bacterial compartmentalization result in abnormal colonization of posterior midgut regions by pathogenic bacteria. Despite a functional IMD pathway, this ectopic colonization leads to bacterial proliferation and larval death, demonstrating the critical role of bacteria anterior sequestration in larval defense. Our study reveals a temporal orchestration during which pathogenic bacteria, but not innocuous, are confined in the anterior part of the midgut in which they are eliminated in an IMD-pathway-dependent manner.
-
- Cancer Biology
- Cell Biology
Understanding the cell cycle at the single-cell level is crucial for cellular biology and cancer research. While current methods using fluorescent markers have improved the study of adherent cells, non-adherent cells remain challenging. In this study, we addressed this gap by combining a specialized surface to enhance cell attachment, the FUCCI(CA)2 sensor, an automated image analysis pipeline, and a custom machine learning algorithm. This approach enabled precise measurement of cell cycle phase durations in non-adherent cells. This method was validated in acute myeloid leukemia cell lines NB4 and Kasumi-1, which have unique cell cycle characteristics, and we tested the impact of cell cycle-modulating drugs on NB4 cells. Our cell cycle analysis system, which is also compatible with adherent cells, is fully automated and freely available, providing detailed insights from hundreds of cells under various conditions. This report presents a valuable tool for advancing cancer research and drug development by enabling comprehensive, automated cell cycle analysis in both adherent and non-adherent cells.
