Tumor-induced myeloid cell plasticity toward lymphatic endothelium

Tumor-associated lymphangiogenesis contributes to tumor progression by
regulating interstitial fluid pressure, transporting immune cells to the tumor site and
providing a route for metastatic dissemination. Metastasis to regional lymph nodes via
lymphatic vessels represents the first step of tumor dissemination in many human
cancers. Therefore, understanding how tumor-associated lymphatic vessels develop may
set the stage for the design of novel anti-metastatic therapy.
Thus far, two mechanisms have been described to drive the formation of new
lymphatic vessels. While it is widely accepted that newly formed lymphatic vessels arise
by sprouting from pre-existing vessels, the recently described context-dependent
integration and thus contribution of bone marrow-derived cells to growing lymphatic
vessels is rather controversial.
Here, using bone marrow transplantation and lineage-tracing experiments in two
tumor mouse models presenting ongoing lymphangiogenesis, we demonstrate that
myeloid cells can trans-differentiate into lymphatic endothelial cells and thus contribute to
tumor lymphangiogenesis. These data significantly strengthen previous studies on the
controversial role of haematopoietic cells in lymphatic vessel formation and provide new
insights into the development of tumor-associated lymphangiogenesis.
The molecular mechanism underlying the trans-differentiation process remain
unknown. In order to further understand the process, we developed two in vitro assays.
One assay recapitulates the in vivo phenotypical conversion of myeloid cells toward
lymphatic endothelial cells, while the other assay mimicks the in vivo integration of
myeloid cells into lymphatic vessels. The comparison of the transcriptional profiles of
cells at different time points of the in vitro trans-differentiation process revealed timespecific
upregulation of genes representing potential candidates implicated in the
different steps of the process. Both in vitro assays were then used as a tool to assess the
role of selected genes first in the in vitro and then in the in vivo trans-differentiation
process.