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Glutamine-Directed Migration of Cancer-Activated Fibroblasts Facilitates Epithelial Tumor Invasion.

Abstract：

:Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAFs and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration toward this amino acid when cultured in low glutamine conditions. CAFs also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were cocultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation, which involved the TGFβ/Snail1 signaling axis. CAFs moving toward Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells toward nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis. SIGNIFICANCE: Cancer-associated fibroblasts migrate and invade toward free glutamine and facilitate invasion of tumor epithelial cells, accounting for their movement away from the hostile conditions of the tumor towards nutrient-rich adjacent tissues. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/438/F1.large.jpg.

journal_name

Cancer Res

journal_title

Cancer research

authors

Mestre-Farrera A,Bruch-Oms M,Peña R,Rodríguez-Morató J,Alba-Castellón L,Comerma L,Quintela-Fandino M,Duñach M,Baulida J,Pozo ÓJ,García de Herreros A

doi

10.1158/0008-5472.CAN-20-0622

subject

Has Abstract

pub_date

2021-01-15 00:00:00

pages

438-451

issue

2

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-20-0622

journal_volume

81

pub_type

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