TNF-α induces endothelial-mesenchymal transition promoting stromal development of pancreatic adenocarcinoma

Marjorie Adjuto-Saccone; Philippe Soubeyran; Julie Garcia; Stéphane Audebert; Luc Camoin; Marion Rubis; Julie Roques; Bernard Binétruy; Juan Lucio Iovanna; Roselyne Tournaire

doi:10.1038/s41419-021-03920-4

TNF-α induces endothelial-mesenchymal transition promoting stromal development of pancreatic adenocarcinoma

Cell Death Dis. 2021 Jun 25;12(7):649. doi: 10.1038/s41419-021-03920-4.

Affiliations

¹ Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
² Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Marseille Protéomique, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
³ INMED, INSERM U1249, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France.
⁴ Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. roselyne.tournaire@inserm.fr.

Abstract

Endothelial-mesenchymal transition (EndMT) is an important source of cancer-associated fibroblasts (CAFs), which facilitates tumour progression. PDAC is characterised by abundant CAFs and tumour necrosis factor-α (TNF-α). Here, we show that TNF-α strongly induces human endothelial cells to undergo EndMT. Interestingly, TNF-α strongly downregulates the expression of the endothelial receptor TIE1, and reciprocally TIE1 overexpression partially prevents TNF-α-induced EndMT, suggesting that TNF-α acts, at least partially, through TIE1 regulation in this process. We also show that TNF-α-induced EndMT is reversible. Furthermore, TNF-α treatment of orthotopic mice resulted in an important increase in the stroma, including CAFs. Finally, secretome analysis identified TNFSF12, as a regulator that is also present in PDAC patients. With the aim of restoring normal angiogenesis and better access to drugs, our results support the development of therapies targeting CAFs or inducing the EndMT reversion process in PDAC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cancer-Associated Fibroblasts / drug effects*
Cancer-Associated Fibroblasts / metabolism
Cancer-Associated Fibroblasts / pathology
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology*
Cells, Cultured
Cytokine TWEAK / genetics
Cytokine TWEAK / metabolism
Endothelial Cells / drug effects*
Endothelial Cells / metabolism
Endothelial Cells / pathology
Epithelial-Mesenchymal Transition / drug effects*
Humans
Male
Mice, Transgenic
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology*
Receptor, TIE-1 / genetics
Receptor, TIE-1 / metabolism
Snail Family Transcription Factors / genetics
Snail Family Transcription Factors / metabolism
Tumor Necrosis Factor-alpha / pharmacology*
Zinc Finger E-box Binding Homeobox 2 / genetics
Zinc Finger E-box Binding Homeobox 2 / metabolism

Substances

Cytokine TWEAK
Snail Family Transcription Factors
TNF protein, human
TNFSF12 protein, human
Tnf protein, mouse
Tumor Necrosis Factor-alpha
ZEB2 protein, human
Zinc Finger E-box Binding Homeobox 2
Receptor, TIE-1
TIE1 protein, human