Oncogenic PIK3CA mutations shape an immunoregulatory microenvironment in mosaic overgrowth disorders
Abstract
PIK3CA-related overgrowth spectrum (PROS) comprises a group of rare genetic disorders caused by de novo, mosaic, postzygotic gain-of-function mutations in the PIK3CA gene. These mutations arise during embryogenesis, affect multiple organ systems, and result in heterogeneous clinical phenotypes. We previously showed that primary cells derived from a PROS mouse model exhibit a metabolic shift toward aerobic glycolysis (a Warburg-like effect), accompanied by altered secretion of metabolites. Here, we observed that this metabolic reprogramming was associated with the up-regulation of key transcription factors, including cellular myelocytomatosis and hypoxia-inducible factor 1 alpha. PIK3CA hyperactivation induces a distinct microenvironment marked by metabolic dysregulation, extracellular matrix remodeling, increased cellular proliferation, elevated phosphorylated form of the histone variant H2AX levels, and enhanced macrophage infiltration, hallmarks commonly associated with increased lactate production. To further examine immune infiltration dynamics, we used a mouse model expressing a constitutively active PIK3CA mutation selectively in adipose tissue (AdipoCreER), a tissue frequently affected in PROS. Single-cell transcriptomics and flow cytometry profiling revealed that macrophages adopt an immunomodulatory phenotype, with increased infiltration of TREM2+ and Lyve1hiMHCIIlo macrophages, along with myeloid-derived suppressor cells, and a concurrent reduction in T-cell populations. These immune alterations parallel those observed in tumor microenvironments and may contribute to tissue overgrowth and impaired immune surveillance. Multiplex immunofluorescence analysis of tissue samples from individuals with PROS confirmed these findings, underscoring the translational relevance of the mouse model. Together, our results demonstrate that PIK3CA mutations in PROS profoundly remodel the tissue microenvironment and reprogram macrophage function in a manner reminiscent of tumor biology.
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BibTeX
@article{galasso2026oncogenic,
title = {{Oncogenic PIK3CA mutations shape an immunoregulatory microenvironment in mosaic overgrowth disorders}},
author = {Ilaria Galasso and Charles Bayard and Camille Blériot and Sophia Ladraa and Wan Ting Kong and Rubina Cassaca and Clément Hoguin and Sanela Protic and Jérôme Megret and Nicolas Goudin and Nicolas Signolle and Jean-Yves Scoazec and Ivan Nemazanyy and Estelle Balducci and Patrick Villarese and Vahid Asnafi and Sylvie Fraitag and Nicolas Venteclef and Florent Ginhoux and Guillaume Canaud},
journal = {PNAS Nexus},
year = {2026},
month = may,
doi = {10.1093/pnasnexus/pgag163},
url = {https://hal.science/hal-05762931v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Oncogenic PIK3CA mutations shape an immunoregulatory microenvironment in mosaic overgrowth disorders
AU - Ilaria Galasso
AU - Charles Bayard
AU - Camille Blériot
AU - Sophia Ladraa
AU - Wan Ting Kong
AU - Rubina Cassaca
AU - Clément Hoguin
AU - Sanela Protic
AU - Jérôme Megret
AU - Nicolas Goudin
AU - Nicolas Signolle
AU - Jean-Yves Scoazec
AU - Ivan Nemazanyy
AU - Estelle Balducci
AU - Patrick Villarese
AU - Vahid Asnafi
AU - Sylvie Fraitag
AU - Nicolas Venteclef
AU - Florent Ginhoux
AU - Guillaume Canaud
PY - 2026
DA - 2026/05/13
JO - PNAS Nexus
DO - 10.1093/pnasnexus/pgag163
UR - https://hal.science/hal-05762931v1
AB - PIK3CA-related overgrowth spectrum (PROS) comprises a group of rare genetic disorders caused by de novo, mosaic, postzygotic gain-of-function mutations in the PIK3CA gene. These mutations arise during embryogenesis, affect multiple organ systems, and result in heterogeneous clinical phenotypes. We previously showed that primary cells derived from a PROS mouse model exhibit a metabolic shift toward aerobic glycolysis (a Warburg-like effect), accompanied by altered secretion of metabolites. Here, we observed that this metabolic reprogramming was associated with the up-regulation of key transcription factors, including cellular myelocytomatosis and hypoxia-inducible factor 1 alpha. PIK3CA hyperactivation induces a distinct microenvironment marked by metabolic dysregulation, extracellular matrix remodeling, increased cellular proliferation, elevated phosphorylated form of the histone variant H2AX levels, and enhanced macrophage infiltration, hallmarks commonly associated with increased lactate production. To further examine immune infiltration dynamics, we used a mouse model expressing a constitutively active PIK3CA mutation selectively in adipose tissue (AdipoCreER), a tissue frequently affected in PROS. Single-cell transcriptomics and flow cytometry profiling revealed that macrophages adopt an immunomodulatory phenotype, with increased infiltration of TREM2+ and Lyve1hiMHCIIlo macrophages, along with myeloid-derived suppressor cells, and a concurrent reduction in T-cell populations. These immune alterations parallel those observed in tumor microenvironments and may contribute to tissue overgrowth and impaired immune surveillance. Multiplex immunofluorescence analysis of tissue samples from individuals with PROS confirmed these findings, underscoring the translational relevance of the mouse model. Together, our results demonstrate that PIK3CA mutations in PROS profoundly remodel the tissue microenvironment and reprogram macrophage function in a manner reminiscent of tumor biology.
SN - 2752-6542
ER -