TY - JOUR
T1 - Glutamine-Directed Migration of Cancer-Activated Fibroblasts Facilitates Epithelial Tumor Invasion
AU - Mestre-Farrera, Aida
AU - Bruch-Oms, Marina
AU - Peña, Raúl
AU - Rodríguez-Morató, José
AU - Alba-Castellón, Lorena
AU - Comerma, Laura
AU - Quintela-Fandino, Miguel
AU - Duñach, Mireia
AU - Baulida, Josep
AU - Pozo, Óscar J.
AU - García de Herreros, Antonio
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/23
Y1 - 2020/11/23
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Breast Neoplasms/drug therapy
KW - Cancer-Associated Fibroblasts/drug effects
KW - Cell Movement
KW - Cell Proliferation
KW - Epithelial-Mesenchymal Transition
KW - Female
KW - Glutamine/pharmacology
KW - Humans
KW - Mice
KW - Mice, Nude
KW - Neoplasms, Glandular and Epithelial/drug therapy
KW - Tumor Cells, Cultured
KW - Xenograft Model Antitumor Assays
KW - AKT2
KW - GROWTH
KW - COMPLEX
KW - SNAIL1
KW - MESENCHYMAL STEM-CELLS
KW - AMINO-ACID
KW - TRAF6
KW - RESISTANCE
KW - DIFFERENTIATION
KW - EXPRESSION
UR - https://doi.org/10.1158/0008-5472.CAN-20-0622
UR - http://www.scopus.com/inward/record.url?scp=85100388254&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/bdb2f80d-ac60-39e6-8b9b-44a2b2fd20f2/
U2 - 10.1158/0008-5472.can-20-0622
DO - 10.1158/0008-5472.can-20-0622
M3 - Article
C2 - 33229340
VL - 81
SP - 438
EP - 451
IS - 2
ER -