Glutamine-directed migration of cancer-activated fibroblasts facilitates epithelial tumor invasion

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• dc.contributor.author Mestre-Farrera, Aida, 1992-
• dc.contributor.author Bruch-Oms, Marina
• dc.contributor.author Peña Arranz, Raúl, 1976-
• dc.contributor.author Rodríguez-Morató, Jose, 1987-
• dc.contributor.author Alba Castellón, Lorena, 1984-
• dc.contributor.author Comerma Blesa, Laura, 1983-
• dc.contributor.author Quintela-Fandino, Miguel
• dc.contributor.author Duñach, Mireia
• dc.contributor.author Baulida i Estadella, Josep, 1965-
• dc.contributor.author Pozo Mendoza, Óscar J., 1975-
• dc.contributor.author García de Herreros, Antonio
• dc.date.accessioned 2021-06-04T07:05:08Z
• dc.date.issued 2021
• dc.description.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.
• dc.description.sponsorship We thank Drs. J. Moscat for advice, J. Yélamos, M. Birnbaum and L. Tío for cell lines and reagents and M. Iglesias for assistance. This study was funded by grants awarded by Ministerio de Ciencia, Innovación y Universidades -Agencia Estatal de Investigación (Retos de Investigación) and FEDER (SAF2016-76461-R and PID2019-104698RB-I00 to AGH and RTI2018-099719-B-100 to MD). We also acknowledge support from the Instituto Carlos III (PIE15/00008). AMF was funded by a Predoctoral FI Contract by the Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement de la Generalitat de Catalunya (FI-DGR 2016); MBO and LAC were recipients of FPI contracts awarded by Ministerio de Ciencia y Tecnologia.
• dc.format.mimetype application/pdf
• dc.identifier.citation Mestre-Farrera A, Bruch-Oms M, Peña R, Rodríguez-Morató J, Alba-Castellón L, Comerma L, et al. Glutamine-directed migration of cancer-activated fibroblasts facilitates epithelial tumor invasion. Cancer Res. 2021 Jan 15; 81(2): 438-51. DOI: 10.1158/0008-5472.CAN-20-0622
• dc.identifier.doi http://dx.doi.org/10.1158/0008-5472.CAN-20-0622
• dc.identifier.issn 0008-5472
• dc.identifier.uri http://hdl.handle.net/10230/47761
• dc.language.iso eng
• dc.publisher American Association for Cancer Research (AACR)
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-76461-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019- 104698RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-099719-B-100t
• dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/0008-5472.CAN-20-0622
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Glutamina
• dc.subject.other Mama--Càncer--Tractament
• dc.subject.other Mama--Càncer--Aspectes genètics
• dc.subject.other Tumors
• dc.title Glutamine-directed migration of cancer-activated fibroblasts facilitates epithelial tumor invasion
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion