Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion

Elizabeth R Murray; Shinelle Menezes; Jack C Henry; Josie L Williams; Lorena Alba-Castellón; Priththivika Baskaran; Ivan Quétier; Ami Desai; Jacqueline J T Marshall; Ian Rosewell; Marianthi Tatari; Vinothini Rajeeve; Faraz Khan; Jun Wang; Panoraia Kotantaki; Eleanor J Tyler; Namrata Singh; Claire S Reader; Edward P Carter; Kairbaan Hodivala-Dilke; Richard P Grose; Hemant M Kocher; Nuria Gavara; Oliver Pearce; Pedro Cutillas; John F Marshall; Angus J M Cameron

doi:10.1016/j.celrep.2021.110227

Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion

Elizabeth R Murray, Shinelle Menezes, Jack C Henry, Josie L Williams, Lorena Alba-Castellón, Priththivika Baskaran, Ivan Quétier, Ami Desai, Jacqueline J T Marshall, Ian Rosewell, Marianthi Tatari, Vinothini Rajeeve, Faraz Khan, Jun Wang, Panoraia Kotantaki, Eleanor J Tyler, Namrata Singh, Claire S Reader, Edward P Carter, Kairbaan Hodivala-DilkeRichard P Grose, Hemant M Kocher, Nuria Gavara, Oliver Pearce, Pedro Cutillas, John F Marshall, Angus J M Cameron

Department of Life Sciences

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

47 Citations (SciVal)

Abstract

In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

Original language	English
Pages (from-to)	110227
Journal	Cell Reports
Volume	38
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2021.110227
Publication status	Published - 25 Jan 2022

Bibliographical note

This research was funded by Worldwide Cancer Research/Pancreatic Cancer Research Fund (18-0713), Pancreatic Cancer UK (PCUK2015_A26_Cameron), the Academy of Medical Sciences (SBF001\1004), The Royal Society (RG140568), Barts Charity (MGU0605), and Cancer Research UK Center Grants to Barts Cancer Institute (C355/A25137) and the City of London Centre (C7893/A26233); E.R.M. and J.C.H. were funded by Cancer Research UK studentships (C16420/A20916 and C355/A29277) and the Rosetrees Trust (M483). J.L.W. is supported by a BBSRC/AstraZeneca iCASE/LIDo studentship, and P.B. was supported by an MRC studentship to QMUL.

Data and code availability
•
RNA-sequencing data has been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. Western blot and microscopy data are available upon request from the lead contact. This paper also analyzes existing, publicly available data. These accession numbers for the datasets are listed in the key resources table.

•
All original code has been deposited at Github and is publicly available as of the date of publication. DOIs are listed in the key resources table.

•
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Keywords

Animals
Humans
Mice
Neoplasm Invasiveness/pathology
Pancreatic Neoplasms/pathology
Pancreatic Stellate Cells/metabolism
Phenotype
Protein Kinase C/metabolism
Tumor Microenvironment/physiology

UN SDGs

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

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10.1016/j.celrep.2021.110227Licence: CC BY

Cite this

Murray, E. R., Menezes, S., Henry, J. C., Williams, J. L., Alba-Castellón, L., Baskaran, P., Quétier, I., Desai, A., Marshall, J. J. T., Rosewell, I., Tatari, M., Rajeeve, V., Khan, F., Wang, J., Kotantaki, P., Tyler, E. J., Singh, N., Reader, C. S., Carter, E. P., ... Cameron, A. J. M. (2022). Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion. Cell Reports, 38(4), 110227. https://doi.org/10.1016/j.celrep.2021.110227

Murray, ER, Menezes, S, Henry, JC, Williams, JL, Alba-Castellón, L, Baskaran, P, Quétier, I, Desai, A, Marshall, JJT, Rosewell, I, Tatari, M, Rajeeve, V, Khan, F, Wang, J, Kotantaki, P, Tyler, EJ, Singh, N, Reader, CS, Carter, EP, Hodivala-Dilke, K, Grose, RP, Kocher, HM, Gavara, N, Pearce, O, Cutillas, P, Marshall, JF & Cameron, AJM 2022, 'Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion', Cell Reports, vol. 38, no. 4, pp. 110227. https://doi.org/10.1016/j.celrep.2021.110227

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title = "Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion",

abstract = "In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.",

keywords = "Animals, Humans, Mice, Neoplasm Invasiveness/pathology, Pancreatic Neoplasms/pathology, Pancreatic Stellate Cells/metabolism, Phenotype, Protein Kinase C/metabolism, Tumor Microenvironment/physiology",

author = "Murray, {Elizabeth R} and Shinelle Menezes and Henry, {Jack C} and Williams, {Josie L} and Lorena Alba-Castell{\'o}n and Priththivika Baskaran and Ivan Qu{\'e}tier and Ami Desai and Marshall, {Jacqueline J T} and Ian Rosewell and Marianthi Tatari and Vinothini Rajeeve and Faraz Khan and Jun Wang and Panoraia Kotantaki and Tyler, {Eleanor J} and Namrata Singh and Reader, {Claire S} and Carter, {Edward P} and Kairbaan Hodivala-Dilke and Grose, {Richard P} and Kocher, {Hemant M} and Nuria Gavara and Oliver Pearce and Pedro Cutillas and Marshall, {John F} and Cameron, {Angus J M}",

note = "This research was funded by Worldwide Cancer Research/Pancreatic Cancer Research Fund (18-0713), Pancreatic Cancer UK (PCUK2015_A26_Cameron), the Academy of Medical Sciences (SBF001\1004), The Royal Society (RG140568), Barts Charity (MGU0605), and Cancer Research UK Center Grants to Barts Cancer Institute (C355/A25137) and the City of London Centre (C7893/A26233); E.R.M. and J.C.H. were funded by Cancer Research UK studentships (C16420/A20916 and C355/A29277) and the Rosetrees Trust (M483). J.L.W. is supported by a BBSRC/AstraZeneca iCASE/LIDo studentship, and P.B. was supported by an MRC studentship to QMUL. Data and code availability • RNA-sequencing data has been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. Western blot and microscopy data are available upon request from the lead contact. This paper also analyzes existing, publicly available data. These accession numbers for the datasets are listed in the key resources table. • All original code has been deposited at Github and is publicly available as of the date of publication. DOIs are listed in the key resources table. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.",

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doi = "10.1016/j.celrep.2021.110227",

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T1 - Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion

AU - Murray, Elizabeth R

AU - Menezes, Shinelle

AU - Henry, Jack C

AU - Williams, Josie L

AU - Alba-Castellón, Lorena

AU - Baskaran, Priththivika

AU - Quétier, Ivan

AU - Desai, Ami

AU - Marshall, Jacqueline J T

AU - Rosewell, Ian

AU - Tatari, Marianthi

AU - Rajeeve, Vinothini

AU - Khan, Faraz

AU - Wang, Jun

AU - Kotantaki, Panoraia

AU - Tyler, Eleanor J

AU - Singh, Namrata

AU - Reader, Claire S

AU - Carter, Edward P

AU - Hodivala-Dilke, Kairbaan

AU - Grose, Richard P

AU - Kocher, Hemant M

AU - Gavara, Nuria

AU - Pearce, Oliver

AU - Cutillas, Pedro

AU - Marshall, John F

AU - Cameron, Angus J M

N1 - This research was funded by Worldwide Cancer Research/Pancreatic Cancer Research Fund (18-0713), Pancreatic Cancer UK (PCUK2015_A26_Cameron), the Academy of Medical Sciences (SBF001\1004), The Royal Society (RG140568), Barts Charity (MGU0605), and Cancer Research UK Center Grants to Barts Cancer Institute (C355/A25137) and the City of London Centre (C7893/A26233); E.R.M. and J.C.H. were funded by Cancer Research UK studentships (C16420/A20916 and C355/A29277) and the Rosetrees Trust (M483). J.L.W. is supported by a BBSRC/AstraZeneca iCASE/LIDo studentship, and P.B. was supported by an MRC studentship to QMUL. Data and code availability • RNA-sequencing data has been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. Western blot and microscopy data are available upon request from the lead contact. This paper also analyzes existing, publicly available data. These accession numbers for the datasets are listed in the key resources table. • All original code has been deposited at Github and is publicly available as of the date of publication. DOIs are listed in the key resources table. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

PY - 2022/1/25

Y1 - 2022/1/25

N2 - In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

AB - In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

KW - Animals

KW - Humans

KW - Mice

KW - Neoplasm Invasiveness/pathology

KW - Pancreatic Neoplasms/pathology

KW - Pancreatic Stellate Cells/metabolism

KW - Phenotype

KW - Protein Kinase C/metabolism

KW - Tumor Microenvironment/physiology

U2 - 10.1016/j.celrep.2021.110227

DO - 10.1016/j.celrep.2021.110227

M3 - Article

C2 - 35081338

SN - 2211-1247

VL - 38

SP - 110227

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion

Abstract

Bibliographical note

Keywords

UN SDGs

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