Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation

Nat Commun. 2020 Jun 8;11(1):2869. doi: 10.1038/s41467-020-16496-y.

Abstract

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CAH1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CAH1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics*
  • Cell Movement
  • Child
  • Class I Phosphatidylinositol 3-Kinases / genetics*
  • Endothelial Cells / metabolism
  • Enzyme Activation
  • Female
  • Humans
  • Lymphatic Vessels / abnormalities*
  • Lymphatic Vessels / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Phenotype
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

  • Vascular Endothelial Growth Factor C
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Pik3ca protein, mouse
  • Vascular Endothelial Growth Factor Receptor-3