Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

Emily J. Kay; Karla Paterson; Carla Riero-Domingo; David Sumpton; J. Henry M Däbritz; Saverio Tardito; Claudia Boldrini; Juan R. Hernandez-Fernaud; Dimitris Athineos; Sandeep Dhayade; Ekaterina Stepanova; Enio Gjerga; Lisa J. Neilson; Sergio Lilla; Ann Hedley; Grigorios Koulouras; Grace McGregor; Craig Jamieson; Radia Marie Johnson; Morag Park; Kristina Kirschner; Crispin Miller; Jurre J. Kamphorst; Fabricio Loayza-Puch; Julio Saez-Rodriguez; Massimiliano Mazzone; Karen Blyth; Michele Zagnoni; Sara Zanivan

doi:10.1038/s42255-022-00582-0

Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

Emily J. Kay, Karla Paterson, Carla Riero-Domingo, David Sumpton, J. Henry M Däbritz, Saverio Tardito, Claudia Boldrini, Juan R. Hernandez-Fernaud, Dimitris Athineos, Sandeep Dhayade, Ekaterina Stepanova, Enio Gjerga, Lisa J. Neilson, Sergio Lilla, Ann Hedley, Grigorios Koulouras, Grace McGregor, Craig Jamieson, Radia Marie Johnson, Morag ParkKristina Kirschner, Crispin Miller, Jurre J. Kamphorst, Fabricio Loayza-Puch, Julio Saez-Rodriguez, Massimiliano Mazzone, Karen Blyth, Michele Zagnoni, Sara Zanivan

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

13 Downloads (Pure)

Abstract

Elevated production of collagen-rich extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a central driver of cancer aggressiveness. Here we find that proline, a highly abundant amino acid in collagen proteins, is newly synthesized from glutamine in CAFs to make tumour collagen in breast cancer xenografts. PYCR1 is a key enzyme for proline synthesis and highly expressed in the stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reduce tumour collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. Both collagen and glutamine-derived proline synthesis in CAFs are epigenetically upregulated by increased pyruvate dehydrogenase-derived acetyl-CoA levels. PYCR1 is a cancer cell vulnerability and potential target for therapy; therefore, our work provides evidence that targeting PYCR1 may have the additional benefit of halting the production of a pro-tumorigenic extracellular matrix. Our work unveils new roles for CAF metabolism to support pro-tumorigenic collagen production.

Original language	English
Pages (from-to)	693-710
Number of pages	18
Journal	Nature metabolism
Volume	4
Issue number	6
DOIs	https://doi.org/10.1038/s42255-022-00582-0
Publication status	Published - 27 Jun 2022

Keywords

cancer-associated fibroblasts - metabolism - pathology
collagen - metabolism
breast neoplasms - metabolism
carcinogenesis - metabolism - pathology
humans
female
glutamine - metabolism
proline
pyrroline carboxylate reductases - metabolism
extracellular matrix - metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s42255-022-00582-0Licence: CC BY 4.0

Kay-etal-NM-2022-Cancer-associated-fibroblasts-require-proline-synthesis-by-PYCR1-for-the-depositionFinal published version, 9.21 MBLicence: CC BY 4.0

32 Citations
1 Comment/debate

Author correction: Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix
Kay, E. J., Paterson, K., Riera-Domingo, C., Sumpton, D., Däbritz, J. H. M., Tardito, S., Boldrini, C., Hernandez-Fernaud, J. R., Athineos, D., Dhayade, S., Stepanova, E., Gjerga, E., Neilson, L. J., Lilla, S., Hedley, A., Koulouras, G., McGregor, G., Jamieson, C., Johnson, R. M., Park, M., & 9 othersKirschner, K., Miller, C., Kamphorst, J. J., Loayza-Puch, F., Saez-Rodriguez, J., Mazzone, M., Blyth, K., Zagnoni, M. & Zanivan, S., 4 Aug 2022, In: Nature metabolism. 4, 8, p. 1084-1084 1 p.
Research output: Contribution to journal › Comment/debate › peer-review

Open Access
File
1 Citation (Scopus)

5 Downloads (Pure)

Cite this

Kay, E. J., Paterson, K., Riero-Domingo, C., Sumpton, D., Däbritz, J. H. M., Tardito, S., Boldrini, C., Hernandez-Fernaud, J. R., Athineos, D., Dhayade, S., Stepanova, E., Gjerga, E., Neilson, L. J., Lilla, S., Hedley, A., Koulouras, G., McGregor, G., Jamieson, C., Johnson, R. M., ... Zanivan, S. (2022). Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature metabolism, 4(6), 693-710. https://doi.org/10.1038/s42255-022-00582-0

@article{52f5f963c88d47c9ac82d3185d7a8af1,

title = "Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix",

abstract = "Elevated production of collagen-rich extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a central driver of cancer aggressiveness. Here we find that proline, a highly abundant amino acid in collagen proteins, is newly synthesized from glutamine in CAFs to make tumour collagen in breast cancer xenografts. PYCR1 is a key enzyme for proline synthesis and highly expressed in the stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reduce tumour collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. Both collagen and glutamine-derived proline synthesis in CAFs are epigenetically upregulated by increased pyruvate dehydrogenase-derived acetyl-CoA levels. PYCR1 is a cancer cell vulnerability and potential target for therapy; therefore, our work provides evidence that targeting PYCR1 may have the additional benefit of halting the production of a pro-tumorigenic extracellular matrix. Our work unveils new roles for CAF metabolism to support pro-tumorigenic collagen production.",

keywords = "cancer-associated fibroblasts - metabolism - pathology, collagen - metabolism, breast neoplasms - metabolism, carcinogenesis - metabolism - pathology, humans, female, glutamine - metabolism, proline, pyrroline carboxylate reductases - metabolism, extracellular matrix - metabolism",

author = "Kay, {Emily J.} and Karla Paterson and Carla Riero-Domingo and David Sumpton and D{\"a}britz, {J. Henry M} and Saverio Tardito and Claudia Boldrini and Hernandez-Fernaud, {Juan R.} and Dimitris Athineos and Sandeep Dhayade and Ekaterina Stepanova and Enio Gjerga and Neilson, {Lisa J.} and Sergio Lilla and Ann Hedley and Grigorios Koulouras and Grace McGregor and Craig Jamieson and Johnson, {Radia Marie} and Morag Park and Kristina Kirschner and Crispin Miller and Kamphorst, {Jurre J.} and Fabricio Loayza-Puch and Julio Saez-Rodriguez and Massimiliano Mazzone and Karen Blyth and Michele Zagnoni and Sara Zanivan",

year = "2022",

month = jun,

day = "27",

doi = "10.1038/s42255-022-00582-0",

language = "English",

volume = "4",

pages = "693--710",

number = "6",

}

Kay, EJ, Paterson, K, Riero-Domingo, C, Sumpton, D, Däbritz, JHM, Tardito, S, Boldrini, C, Hernandez-Fernaud, JR, Athineos, D, Dhayade, S, Stepanova, E, Gjerga, E, Neilson, LJ, Lilla, S, Hedley, A, Koulouras, G, McGregor, G, Jamieson, C, Johnson, RM, Park, M, Kirschner, K, Miller, C, Kamphorst, JJ, Loayza-Puch, F, Saez-Rodriguez, J, Mazzone, M, Blyth, K, Zagnoni, M & Zanivan, S 2022, 'Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix', Nature metabolism, vol. 4, no. 6, pp. 693-710. https://doi.org/10.1038/s42255-022-00582-0

TY - JOUR

T1 - Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

AU - Kay, Emily J.

AU - Paterson, Karla

AU - Riero-Domingo, Carla

AU - Sumpton, David

AU - Däbritz, J. Henry M

AU - Tardito, Saverio

AU - Boldrini, Claudia

AU - Hernandez-Fernaud, Juan R.

AU - Athineos, Dimitris

AU - Dhayade, Sandeep

AU - Stepanova, Ekaterina

AU - Gjerga, Enio

AU - Neilson, Lisa J.

AU - Lilla, Sergio

AU - Hedley, Ann

AU - Koulouras, Grigorios

AU - McGregor, Grace

AU - Jamieson, Craig

AU - Johnson, Radia Marie

AU - Park, Morag

AU - Kirschner, Kristina

AU - Miller, Crispin

AU - Kamphorst, Jurre J.

AU - Loayza-Puch, Fabricio

AU - Saez-Rodriguez, Julio

AU - Mazzone, Massimiliano

AU - Blyth, Karen

AU - Zagnoni, Michele

AU - Zanivan, Sara

PY - 2022/6/27

Y1 - 2022/6/27

N2 - Elevated production of collagen-rich extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a central driver of cancer aggressiveness. Here we find that proline, a highly abundant amino acid in collagen proteins, is newly synthesized from glutamine in CAFs to make tumour collagen in breast cancer xenografts. PYCR1 is a key enzyme for proline synthesis and highly expressed in the stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reduce tumour collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. Both collagen and glutamine-derived proline synthesis in CAFs are epigenetically upregulated by increased pyruvate dehydrogenase-derived acetyl-CoA levels. PYCR1 is a cancer cell vulnerability and potential target for therapy; therefore, our work provides evidence that targeting PYCR1 may have the additional benefit of halting the production of a pro-tumorigenic extracellular matrix. Our work unveils new roles for CAF metabolism to support pro-tumorigenic collagen production.

AB - Elevated production of collagen-rich extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a central driver of cancer aggressiveness. Here we find that proline, a highly abundant amino acid in collagen proteins, is newly synthesized from glutamine in CAFs to make tumour collagen in breast cancer xenografts. PYCR1 is a key enzyme for proline synthesis and highly expressed in the stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reduce tumour collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. Both collagen and glutamine-derived proline synthesis in CAFs are epigenetically upregulated by increased pyruvate dehydrogenase-derived acetyl-CoA levels. PYCR1 is a cancer cell vulnerability and potential target for therapy; therefore, our work provides evidence that targeting PYCR1 may have the additional benefit of halting the production of a pro-tumorigenic extracellular matrix. Our work unveils new roles for CAF metabolism to support pro-tumorigenic collagen production.

KW - cancer-associated fibroblasts - metabolism - pathology

KW - collagen - metabolism

KW - breast neoplasms - metabolism

KW - carcinogenesis - metabolism - pathology

KW - humans

KW - female

KW - glutamine - metabolism

KW - proline

KW - pyrroline carboxylate reductases - metabolism

KW - extracellular matrix - metabolism

U2 - 10.1038/s42255-022-00582-0

DO - 10.1038/s42255-022-00582-0

M3 - Article

C2 - 35760868

VL - 4

SP - 693

EP - 710

JO - Nature metabolism

JF - Nature metabolism

IS - 6

ER -

Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Research output

Author correction: Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix

Cite this