Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma

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dc.citation.issueNumber3
dc.citation.journalTitleMolecular Cancer Research
dc.citation.volumeNumber14
dc.contributor.authorPankova, Daniela
dc.contributor.authorChen, Yulong
dc.contributor.authorTerajima, Masahiko
dc.contributor.authorSchliekelman, Mark J.
dc.contributor.authorBaird, Brandi N.
dc.contributor.authorFahrenholtz, Monica
dc.contributor.authorSun, Li
dc.contributor.authorGill, Bartley J.
dc.contributor.authorVadakkan, Tegy J.
dc.contributor.authorKim, Min P.
dc.contributor.authorAhn, Young-Ho
dc.contributor.authorRoybal, Jonathon D.
dc.contributor.authorLiu, Xin
dc.contributor.authorCuentas, Edwin Roger Parra
dc.contributor.authorRodriguez, Jaime
dc.contributor.authorWistuba, Ignacio I.
dc.contributor.authorCreighton, Chad J.
dc.contributor.authorGibbons, Don L.
dc.contributor.authorHicks, John M.
dc.contributor.authorDickinson, Mary E.
dc.contributor.authorWest, Jennifer L.
dc.contributor.authorGrande-Allen, K. Jane
dc.contributor.authorHanash, Samir M.
dc.contributor.authorYamauchi, Mitsuo
dc.contributor.authorKurie, Jonathan M.
dc.date.accessioned2017-05-03T19:58:19Z
dc.date.available2017-05-03T19:58:19Z
dc.date.issued2016
dc.description.abstractIntratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used KrasLA1 mice, which develop lung adenocarcinomas from somatic activation of a KrasG12D allele. The lung tumors in KrasLA1 mice were highly fibrotic and contained cancer-associated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of collagen cross-links was the same in tumors generated with or without CAFs, but coinjected tumors had higher hydroxylysine aldehyde–derived collagen cross-links (HLCC) and lower lysine-aldehyde–derived collagen cross-links (LCCs). Therefore, we postulated that an LCC-to-HLCC switch induced by CAFs promotes the migratory and invasive properties of lung adenocarcinoma cells. To test this hypothesis, we created coculture models in which CAFs are positioned interstitially or peripherally in tumor cell aggregates, mimicking distinct spatial orientations of CAFs in human lung cancer. In both contexts, CAFs enhanced the invasive properties of tumor cells in three-dimensional (3D) collagen gels. Tumor cell aggregates that attached to CAF networks on a Matrigel surface dissociated and migrated on the networks. Lysyl hydroxylase 2 (PLOD2/LH2), which drives HLCC formation, was expressed in CAFs, and LH2 depletion abrogated the ability of CAFs to promote tumor cell invasion and migration.
dc.identifier.citationPankova, Daniela, Chen, Yulong, Terajima, Masahiko, et al.. "Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma." <i>Molecular Cancer Research,</i> 14, no. 3 (2016) American Association for Cancer Research: https://doi.org/10.1158/1541-7786.MCR-15-0307.
dc.identifier.doihttps://doi.org/10.1158/1541-7786.MCR-15-0307
dc.identifier.urihttps://hdl.handle.net/1911/94146
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by AACR.
dc.titleCancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpost-print
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