The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

Claire S. Reader, Sabari Vallath, Colin W. Steele, Syed Haider, Adam Brentnall, Ami Desai, Kate M. Moore, Nigel B. Jamieson, David Chang, Peter Bailey, Aldo Scarpa, Rita Lawlor, Claude Chelala, Stephen M. Keyse, Andrew Biankin, Jennifer P. Morton, T.r. Jeffry Evans, Simon T. Barry, Owen J. Sansom, Hemant M. KocherJohn F. Marshall

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a five‐year survival rate of <4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed high levels of β6 mRNA correlated strongly with significantly poorer survival (n=491 cases, p= 3.17x10‐8). In two separate cohorts we showed that over 80% of PDAC expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p<0.0001) and increased survival (Log‐rank test, p<0.05). Antibody therapy was associated with suppression of both tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated Caspase 3) and suppression of the pro‐tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA‐positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy.
Original languageEnglish
Number of pages11
JournalJournal of Pathology
DOIs
Publication statusE-pub ahead of print - 1 Jul 2019

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Pancreatic Neoplasms
Integrins
Adenocarcinoma
Therapeutics
Growth
gemcitabine
Neoplasms
Cellular Microenvironment
Blocking Antibodies
Tumor Microenvironment
Myofibroblasts
Survival
Heterografts
Caspase 3
Transgenic Mice
Blood Vessels
Cell Survival
Apoptosis
Neoplasm Metastasis
Messenger RNA

Cite this

Reader, Claire S. ; Vallath, Sabari ; Steele, Colin W. ; Haider, Syed ; Brentnall, Adam ; Desai, Ami ; Moore, Kate M. ; Jamieson, Nigel B. ; Chang, David ; Bailey, Peter ; Scarpa, Aldo ; Lawlor, Rita ; Chelala, Claude ; Keyse, Stephen M. ; Biankin, Andrew ; Morton, Jennifer P. ; Evans, T.r. Jeffry ; Barry, Simon T. ; Sansom, Owen J. ; Kocher, Hemant M. ; Marshall, John F. / The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. In: Journal of Pathology. 2019.
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title = "The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) has a five‐year survival rate of <4{\%} and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed high levels of β6 mRNA correlated strongly with significantly poorer survival (n=491 cases, p= 3.17x10‐8). In two separate cohorts we showed that over 80{\%} of PDAC expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p<0.0001) and increased survival (Log‐rank test, p<0.05). Antibody therapy was associated with suppression of both tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated Caspase 3) and suppression of the pro‐tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA‐positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy.",
author = "Reader, {Claire S.} and Sabari Vallath and Steele, {Colin W.} and Syed Haider and Adam Brentnall and Ami Desai and Moore, {Kate M.} and Jamieson, {Nigel B.} and David Chang and Peter Bailey and Aldo Scarpa and Rita Lawlor and Claude Chelala and Keyse, {Stephen M.} and Andrew Biankin and Morton, {Jennifer P.} and Evans, {T.r. Jeffry} and Barry, {Simon T.} and Sansom, {Owen J.} and Kocher, {Hemant M.} and Marshall, {John F.}",
year = "2019",
month = "7",
day = "1",
doi = "10.1002/path.5320",
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Reader, CS, Vallath, S, Steele, CW, Haider, S, Brentnall, A, Desai, A, Moore, KM, Jamieson, NB, Chang, D, Bailey, P, Scarpa, A, Lawlor, R, Chelala, C, Keyse, SM, Biankin, A, Morton, JP, Evans, TRJ, Barry, ST, Sansom, OJ, Kocher, HM & Marshall, JF 2019, 'The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy', Journal of Pathology. https://doi.org/10.1002/path.5320

The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. / Reader, Claire S.; Vallath, Sabari; Steele, Colin W.; Haider, Syed; Brentnall, Adam; Desai, Ami; Moore, Kate M.; Jamieson, Nigel B.; Chang, David; Bailey, Peter; Scarpa, Aldo; Lawlor, Rita; Chelala, Claude; Keyse, Stephen M.; Biankin, Andrew; Morton, Jennifer P.; Evans, T.r. Jeffry; Barry, Simon T.; Sansom, Owen J.; Kocher, Hemant M.; Marshall, John F.

In: Journal of Pathology, 01.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

AU - Reader, Claire S.

AU - Vallath, Sabari

AU - Steele, Colin W.

AU - Haider, Syed

AU - Brentnall, Adam

AU - Desai, Ami

AU - Moore, Kate M.

AU - Jamieson, Nigel B.

AU - Chang, David

AU - Bailey, Peter

AU - Scarpa, Aldo

AU - Lawlor, Rita

AU - Chelala, Claude

AU - Keyse, Stephen M.

AU - Biankin, Andrew

AU - Morton, Jennifer P.

AU - Evans, T.r. Jeffry

AU - Barry, Simon T.

AU - Sansom, Owen J.

AU - Kocher, Hemant M.

AU - Marshall, John F.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Pancreatic ductal adenocarcinoma (PDAC) has a five‐year survival rate of <4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed high levels of β6 mRNA correlated strongly with significantly poorer survival (n=491 cases, p= 3.17x10‐8). In two separate cohorts we showed that over 80% of PDAC expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p<0.0001) and increased survival (Log‐rank test, p<0.05). Antibody therapy was associated with suppression of both tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated Caspase 3) and suppression of the pro‐tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA‐positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy.

AB - Pancreatic ductal adenocarcinoma (PDAC) has a five‐year survival rate of <4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed high levels of β6 mRNA correlated strongly with significantly poorer survival (n=491 cases, p= 3.17x10‐8). In two separate cohorts we showed that over 80% of PDAC expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p<0.0001) and increased survival (Log‐rank test, p<0.05). Antibody therapy was associated with suppression of both tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated Caspase 3) and suppression of the pro‐tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA‐positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy.

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DO - 10.1002/path.5320

M3 - Article

C2 - 31259422

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

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