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

Daniela Pankova; Yulong Chen; Masahiko Terajima; Mark J Schliekelman; Brandi N Baird; Monica Fahrenholtz; Li Sun; Bartley J Gill; Tegy J Vadakkan; Min P Kim; Young-Ho Ahn; Jonathon D Roybal; Xin Liu; Edwin Roger Parra Cuentas; Jaime Rodriguez; Ignacio I Wistuba; Chad J Creighton; Don L Gibbons; John M Hicks; Mary E Dickinson; Jennifer L West; K Jane Grande-Allen; Samir M Hanash; Mitsuo Yamauchi; Jonathan M Kurie

doi:10.1158/1541-7786.MCR-15-0307

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

Daniela Pankova, Yulong Chen, Masahiko Terajima, Mark J Schliekelman, Brandi N Baird, Monica Fahrenholtz, Li Sun, Bartley J Gill, Tegy J Vadakkan, Min P Kim, Young-Ho Ahn, Jonathon D Roybal, Xin Liu, Edwin Roger Parra Cuentas, Jaime Rodriguez, Ignacio I Wistuba, Chad J Creighton, Don L Gibbons, John M Hicks, Mary E DickinsonJennifer L West, K Jane Grande-Allen, Samir M Hanash, Mitsuo Yamauchi, Jonathan M Kurie

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Abstract

Intratumoral 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 Kras(LA1) mice, which develop lung adenocarcinomas from somatic activation of a Kras(G12D) allele. The lung tumors in Kras(LA1) mice were highly fibrotic and contained cancer-associated fibroblasts (CAFs) 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 co-injected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCCs) 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 co-culture 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 3-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.

IMPLICATIONS: CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells.

Original language	English (US)
Journal	Molecular Cancer Research
DOIs	https://doi.org/10.1158/1541-7786.MCR-15-0307
State	Published - Dec 2 2015

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10.1158/1541-7786.MCR-15-0307

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Pankova, D., Chen, Y., Terajima, M., Schliekelman, M. J., Baird, B. N., Fahrenholtz, M., Sun, L., Gill, B. J., Vadakkan, T. J., Kim, M. P., Ahn, Y.-H., Roybal, J. D., Liu, X., Parra Cuentas, E. R., Rodriguez, J., Wistuba, I. I., Creighton, C. J., Gibbons, D. L., Hicks, J. M., ... Kurie, J. M. (2015). Cancer-associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma. Molecular Cancer Research. https://doi.org/10.1158/1541-7786.MCR-15-0307

Pankova, D, Chen, Y, Terajima, M, Schliekelman, MJ, Baird, BN, Fahrenholtz, M, Sun, L, Gill, BJ, Vadakkan, TJ, Kim, MP, Ahn, Y-H, Roybal, JD, Liu, X, Parra Cuentas, ER, Rodriguez, J, Wistuba, II, Creighton, CJ, Gibbons, DL, Hicks, JM, Dickinson, ME, West, JL, Grande-Allen, KJ, Hanash, SM, Yamauchi, M & Kurie, JM 2015, 'Cancer-associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma', Molecular Cancer Research. https://doi.org/10.1158/1541-7786.MCR-15-0307

@article{6540713821e34ccda17ead76fe8db2a9,

title = "Cancer-associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma",

abstract = "Intratumoral 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 Kras(LA1) mice, which develop lung adenocarcinomas from somatic activation of a Kras(G12D) allele. The lung tumors in Kras(LA1) mice were highly fibrotic and contained cancer-associated fibroblasts (CAFs) 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 co-injected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCCs) 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 co-culture 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 3-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.IMPLICATIONS: CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells.",

author = "Daniela Pankova and Yulong Chen and Masahiko Terajima and Schliekelman, {Mark J} and Baird, {Brandi N} and Monica Fahrenholtz and Li Sun and Gill, {Bartley J} and Vadakkan, {Tegy J} and Kim, {Min P} and Young-Ho Ahn and Roybal, {Jonathon D} and Xin Liu and {Parra Cuentas}, {Edwin Roger} and Jaime Rodriguez and Wistuba, {Ignacio I} and Creighton, {Chad J} and Gibbons, {Don L} and Hicks, {John M} and Dickinson, {Mary E} and West, {Jennifer L} and Grande-Allen, {K Jane} and Hanash, {Samir M} and Mitsuo Yamauchi and Kurie, {Jonathan M}",

note = "Copyright {\textcopyright} 2015, American Association for Cancer Research.",

year = "2015",

month = dec,

day = "2",

doi = "10.1158/1541-7786.MCR-15-0307",

language = "English (US)",

journal = "Molecular Cancer Research",

issn = "1541-7786",

publisher = "American Association for Cancer Research Inc.",

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TY - JOUR

T1 - Cancer-associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma

AU - Pankova, Daniela

AU - Chen, Yulong

AU - Terajima, Masahiko

AU - Schliekelman, Mark J

AU - Baird, Brandi N

AU - Fahrenholtz, Monica

AU - Sun, Li

AU - Gill, Bartley J

AU - Vadakkan, Tegy J

AU - Kim, Min P

AU - Ahn, Young-Ho

AU - Roybal, Jonathon D

AU - Liu, Xin

AU - Parra Cuentas, Edwin Roger

AU - Rodriguez, Jaime

AU - Wistuba, Ignacio I

AU - Creighton, Chad J

AU - Gibbons, Don L

AU - Hicks, John M

AU - Dickinson, Mary E

AU - West, Jennifer L

AU - Grande-Allen, K Jane

AU - Hanash, Samir M

AU - Yamauchi, Mitsuo

AU - Kurie, Jonathan M

PY - 2015/12/2

Y1 - 2015/12/2

N2 - Intratumoral 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 Kras(LA1) mice, which develop lung adenocarcinomas from somatic activation of a Kras(G12D) allele. The lung tumors in Kras(LA1) mice were highly fibrotic and contained cancer-associated fibroblasts (CAFs) 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 co-injected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCCs) 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 co-culture 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 3-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.IMPLICATIONS: CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells.

AB - Intratumoral 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 Kras(LA1) mice, which develop lung adenocarcinomas from somatic activation of a Kras(G12D) allele. The lung tumors in Kras(LA1) mice were highly fibrotic and contained cancer-associated fibroblasts (CAFs) 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 co-injected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCCs) 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 co-culture 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 3-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.IMPLICATIONS: CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells.

U2 - 10.1158/1541-7786.MCR-15-0307

DO - 10.1158/1541-7786.MCR-15-0307

M3 - Article

C2 - 26631572

SN - 1541-7786

JO - Molecular Cancer Research

JF - Molecular Cancer Research

ER -

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

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