Targeting PI3K/AKT/mTOR Pathway Exerts Inhibitory Effects on Endothelial Cells from Generalized Lymphatic Anomaly
6 affiliations
- 1Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- 2Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy
- 3Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy
- 4Dental School, University of Parma Medical School, 43126 Parma, Italy
- 5Pathology Unit, University Hospital of Parma, 43126 Parma, Italy
- 6Pediatric Surgery, Ospedale dei Bambini of Parma, University Hospital of Parma, 43126 Parma, Italy
Abstract
Generalized lymphatic anomaly (GLA) is a congenital, non-neoplastic vascular anomaly characterized by diffuse or multifocal involvement and infiltration of multiple organs. Most GLA cases harbor “hotspot” somatic missense single nucleotide mutations in the PIK3CA gene, whereas a minority involve mutations in other genes. Recently, rapamycin and its homologs have shown encouraging results in the treatment of alterations affecting the PI3K/AKT/mTOR pathway. Therefore, the present work aimed to expand the immunophenotypic characterization of the lymphatic lesion at the tissue level and to evaluate the in vitro viability, migration, and angiogenic capacity of endothelial cells freshly isolated from a PIK3CA-mutated GLA sample, following treatment with alpelisib, rapamycin, dactolisib, and buparlisib. We detected the p.Gln546Lys amino acid substitution in the PI3Kca helical domain in GLA-derived endothelial cells. Then, by immunohistochemical analysis, we documented altered expression of mTOR and its well-characterized downstream substrates, which regulate growth, proliferation, migration, angiogenesis, and survival of ECs. Finally, pharmacological treatment reduced GLA-EC functional properties and down-modulated the hyperactivated PI3K downstream substrates. Overall, our results suggest that routine immunohistochemistry, integrated with phospho-protein analysis and next-generation sequencing, might improve histopathological classification of vascular anomalies and facilitate the development of personalized targeted therapies, particularly in recurrent or surgically challenging cases.
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BibTeX
@article{lorusso2026targeting,
title = {{Targeting PI3K/AKT/mTOR Pathway Exerts Inhibitory Effects on Endothelial Cells from Generalized Lymphatic Anomaly}},
author = {Bruno Lorusso and Laura Finato and Antonella Nogara and Giovanni Roti and Anna Montanaro and Gregorio Monica and Alice Andreani and Gallia Graiani and Pellegrino Crafa and Enrico Maria Silini and Letizia Gnetti and Francesco Paolo Pilato and Lorena Bottarelli and Cinzia Azzoni and Giuseppe Cerasoli and Federico Quaini and Costanza Anna Maria Lagrasta},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201860},
url = {https://www.mdpi.com/2073-4409/15/20/1860},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting PI3K/AKT/mTOR Pathway Exerts Inhibitory Effects on Endothelial Cells from Generalized Lymphatic Anomaly
AU - Bruno Lorusso
AU - Laura Finato
AU - Antonella Nogara
AU - Giovanni Roti
AU - Anna Montanaro
AU - Gregorio Monica
AU - Alice Andreani
AU - Gallia Graiani
AU - Pellegrino Crafa
AU - Enrico Maria Silini
AU - Letizia Gnetti
AU - Francesco Paolo Pilato
AU - Lorena Bottarelli
AU - Cinzia Azzoni
AU - Giuseppe Cerasoli
AU - Federico Quaini
AU - Costanza Anna Maria Lagrasta
PY - 2026
DA - 2026/10/13
JO - Cells
DO - 10.3390/cells15201860
UR - https://www.mdpi.com/2073-4409/15/20/1860
AB - Generalized lymphatic anomaly (GLA) is a congenital, non-neoplastic vascular anomaly characterized by diffuse or multifocal involvement and infiltration of multiple organs. Most GLA cases harbor “hotspot” somatic missense single nucleotide mutations in the PIK3CA gene, whereas a minority involve mutations in other genes. Recently, rapamycin and its homologs have shown encouraging results in the treatment of alterations affecting the PI3K/AKT/mTOR pathway. Therefore, the present work aimed to expand the immunophenotypic characterization of the lymphatic lesion at the tissue level and to evaluate the in vitro viability, migration, and angiogenic capacity of endothelial cells freshly isolated from a PIK3CA-mutated GLA sample, following treatment with alpelisib, rapamycin, dactolisib, and buparlisib. We detected the p.Gln546Lys amino acid substitution in the PI3Kca helical domain in GLA-derived endothelial cells. Then, by immunohistochemical analysis, we documented altered expression of mTOR and its well-characterized downstream substrates, which regulate growth, proliferation, migration, angiogenesis, and survival of ECs. Finally, pharmacological treatment reduced GLA-EC functional properties and down-modulated the hyperactivated PI3K downstream substrates. Overall, our results suggest that routine immunohistochemistry, integrated with phospho-protein analysis and next-generation sequencing, might improve histopathological classification of vascular anomalies and facilitate the development of personalized targeted therapies, particularly in recurrent or surgically challenging cases.
SN - 2073-4409
ER -