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

Aida Mestre-Farrera, Marina Bruch-Oms, Raúl Peña, José Rodríguez-Morató, Lorena Alba-Castellón, Laura Comerma, Miguel Quintela-Fandino, Mireia Duñach, Josep Baulida, Óscar J. Pozo, Antonio García de Herreros

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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 TGFb/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.

Original languageEnglish
Pages (from-to)438-451
Number of pages14
JournalCancer Research
Volume81
Issue number2
DOIs
Publication statusPublished - 23 Nov 2020

Keywords

  • Animals
  • Apoptosis
  • Breast Neoplasms/drug therapy
  • Cancer-Associated Fibroblasts/drug effects
  • Cell Movement
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Female
  • Glutamine/pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms, Glandular and Epithelial/drug therapy
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • AKT2
  • GROWTH
  • COMPLEX
  • SNAIL1
  • MESENCHYMAL STEM-CELLS
  • AMINO-ACID
  • TRAF6
  • RESISTANCE
  • DIFFERENTIATION
  • EXPRESSION

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