Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

Dror Kolodkin-Gal; Lior Roitman; Yossi Ovadya; Narmen Azazmeh; Benjamin Assouline; Yehuda Schlesinger; Rachel Kalifa; Shaul Horwitz; Yonatan Khalatnik; Anna Hochner-Ger; Ashraf Imam; Jonathan Abraham Demma; Eitan Winter; Hadar Benyamini; Sharona Elgavish; Areej A.S. Khatib; Karen Meir; Karine Atlan; Eli Pikarsky; Oren Parnas; Yuval Dor; Gideon Zamir; Ittai Ben-Porath; Valery Krizhanovsky

doi:10.1136/gutjnl-2020-321112

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

Dror Kolodkin-Gal, Lior Roitman, Yossi Ovadya, Narmen Azazmeh, Benjamin Assouline, Yehuda Schlesinger, Rachel Kalifa, Shaul Horwitz, Yonatan Khalatnik, Anna Hochner-Ger, Ashraf Imam, Jonathan Abraham Demma, Eitan Winter, Hadar Benyamini, Sharona Elgavish, Areej A.S. Khatib, Karen Meir, Karine Atlan, Eli Pikarsky, Oren ParnasYuval Dor^*, Gideon Zamir, Ittai Ben-Porath, Valery Krizhanovsky

^*Corresponding author for this work

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

19 Scopus citations

Abstract

Objective Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. Design To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. Results We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. Conclusions These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

Original language	American English
Pages (from-to)	345-355
Number of pages	11
Journal	Gut
Volume	71
Issue number	2
DOIs	https://doi.org/10.1136/gutjnl-2020-321112
State	Published - 1 Feb 2022

Bibliographical note

Funding Information:
This study was supported by donations from Barbara R. Newman in memory of Daniel Newman (GZ), Brenda B. Johnston in memory of Theodore A. Johnston (GZ), and grants from the Israel Science Foundation (1009/13, IB-P), the Israel Science Foundation Morasha programme (1245/16, IB-P.), the Israel Science Foundation-Broad Institute programme (2621/18, IB-P.), the Chief Scientist of the Israel Ministry of Health (3-15017, IB-P), the Alex U. Soyka Programme (IB-P and YD) the Israel Cancer Research Fund (ICRF) Project Grant (GZ), the Israel Science Foundation-Canada programme (2633/17, VK), Sagol Institute for Longevity Research, QuinQuin Foundation, Rising Tide Foundation and Thompson Family Foundation (VK) and the European Research Council under the European Union's FP7 and H2020 (309688 and 856487, VK).

Funding Information:
Funding This study was supported by donations from Barbara R. Newman in memory of Daniel Newman (GZ), Brenda B. Johnston in memory of Theodore A. Johnston (GZ), and grants from the Israel Science Foundation (1009/13, IB-P), the Israel Science Foundation Morasha programme (1245/16, IB-P.), the Israel Science Foundation-Broad Institute programme (2621/18, IB-P.), the Chief Scientist of the Israel Ministry of Health (3–15017, IB-P), the Alex U. Soyka Programme (IB-P and YD) the Israel Cancer Research Fund (ICRF) Project Grant (GZ), the Israel Science Foundation-Canada programme (2633/17, VK), Sagol Institute for Longevity Research, QuinQuin Foundation, Rising Tide Foundation and Thompson Family Foundation (VK) and the European Research Council under the European Union’s FP7 and H2020 (309688 and 856487, VK).

Publisher Copyright:
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

Adenocarcinoma/metabolism
Animals
Cellular Senescence/drug effects
Cyclooxygenase 2/metabolism
Disease Models, Animal
Mice
Pancreatic Neoplasms/metabolism
Precancerous Conditions/metabolism
Senotherapeutics/therapeutic use

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10.1136/gutjnl-2020-321112

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Kolodkin-Gal, D., Roitman, L., Ovadya, Y., Azazmeh, N., Assouline, B., Schlesinger, Y., Kalifa, R., Horwitz, S., Khalatnik, Y., Hochner-Ger, A., Imam, A., Demma, J. A., Winter, E., Benyamini, H., Elgavish, S., Khatib, A. A. S., Meir, K., Atlan, K., Pikarsky, E., ... Krizhanovsky, V. (2022). Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions. Gut, 71(2), 345-355. https://doi.org/10.1136/gutjnl-2020-321112

@article{53062cc8432a44f9a02f1287ebbe1d72,

title = "Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions",

abstract = "Objective Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. Design To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. Results We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. Conclusions These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.",

keywords = "Adenocarcinoma/metabolism, Animals, Cellular Senescence/drug effects, Cyclooxygenase 2/metabolism, Disease Models, Animal, Mice, Pancreatic Neoplasms/metabolism, Precancerous Conditions/metabolism, Senotherapeutics/therapeutic use",

author = "Dror Kolodkin-Gal and Lior Roitman and Yossi Ovadya and Narmen Azazmeh and Benjamin Assouline and Yehuda Schlesinger and Rachel Kalifa and Shaul Horwitz and Yonatan Khalatnik and Anna Hochner-Ger and Ashraf Imam and Demma, {Jonathan Abraham} and Eitan Winter and Hadar Benyamini and Sharona Elgavish and Khatib, {Areej A.S.} and Karen Meir and Karine Atlan and Eli Pikarsky and Oren Parnas and Yuval Dor and Gideon Zamir and Ittai Ben-Porath and Valery Krizhanovsky",

note = "Funding Information: This study was supported by donations from Barbara R. Newman in memory of Daniel Newman (GZ), Brenda B. Johnston in memory of Theodore A. Johnston (GZ), and grants from the Israel Science Foundation (1009/13, IB-P), the Israel Science Foundation Morasha programme (1245/16, IB-P.), the Israel Science Foundation-Broad Institute programme (2621/18, IB-P.), the Chief Scientist of the Israel Ministry of Health (3-15017, IB-P), the Alex U. Soyka Programme (IB-P and YD) the Israel Cancer Research Fund (ICRF) Project Grant (GZ), the Israel Science Foundation-Canada programme (2633/17, VK), Sagol Institute for Longevity Research, QuinQuin Foundation, Rising Tide Foundation and Thompson Family Foundation (VK) and the European Research Council under the European Union's FP7 and H2020 (309688 and 856487, VK). Funding Information: Funding This study was supported by donations from Barbara R. Newman in memory of Daniel Newman (GZ), Brenda B. Johnston in memory of Theodore A. Johnston (GZ), and grants from the Israel Science Foundation (1009/13, IB-P), the Israel Science Foundation Morasha programme (1245/16, IB-P.), the Israel Science Foundation-Broad Institute programme (2621/18, IB-P.), the Chief Scientist of the Israel Ministry of Health (3–15017, IB-P), the Alex U. Soyka Programme (IB-P and YD) the Israel Cancer Research Fund (ICRF) Project Grant (GZ), the Israel Science Foundation-Canada programme (2633/17, VK), Sagol Institute for Longevity Research, QuinQuin Foundation, Rising Tide Foundation and Thompson Family Foundation (VK) and the European Research Council under the European Union{\textquoteright}s FP7 and H2020 (309688 and 856487, VK). Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = feb,

day = "1",

doi = "10.1136/gutjnl-2020-321112",

language = "American English",

volume = "71",

pages = "345--355",

journal = "Gut",

issn = "0017-5749",

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Kolodkin-Gal, D, Roitman, L, Ovadya, Y, Azazmeh, N, Assouline, B, Schlesinger, Y, Kalifa, R, Horwitz, S, Khalatnik, Y, Hochner-Ger, A, Imam, A, Demma, JA, Winter, E, Benyamini, H, Elgavish, S, Khatib, AAS, Meir, K, Atlan, K, Pikarsky, E , Parnas, O , Dor, Y, Zamir, G, Ben-Porath, I & Krizhanovsky, V 2022, 'Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions', Gut, vol. 71, no. 2, pp. 345-355. https://doi.org/10.1136/gutjnl-2020-321112

TY - JOUR

T1 - Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

AU - Kolodkin-Gal, Dror

AU - Roitman, Lior

AU - Ovadya, Yossi

AU - Azazmeh, Narmen

AU - Assouline, Benjamin

AU - Schlesinger, Yehuda

AU - Kalifa, Rachel

AU - Horwitz, Shaul

AU - Khalatnik, Yonatan

AU - Hochner-Ger, Anna

AU - Imam, Ashraf

AU - Demma, Jonathan Abraham

AU - Winter, Eitan

AU - Benyamini, Hadar

AU - Elgavish, Sharona

AU - Khatib, Areej A.S.

AU - Meir, Karen

AU - Atlan, Karine

AU - Pikarsky, Eli

AU - Parnas, Oren

AU - Dor, Yuval

AU - Zamir, Gideon

AU - Ben-Porath, Ittai

AU - Krizhanovsky, Valery

N1 - Funding Information: This study was supported by donations from Barbara R. Newman in memory of Daniel Newman (GZ), Brenda B. Johnston in memory of Theodore A. Johnston (GZ), and grants from the Israel Science Foundation (1009/13, IB-P), the Israel Science Foundation Morasha programme (1245/16, IB-P.), the Israel Science Foundation-Broad Institute programme (2621/18, IB-P.), the Chief Scientist of the Israel Ministry of Health (3-15017, IB-P), the Alex U. Soyka Programme (IB-P and YD) the Israel Cancer Research Fund (ICRF) Project Grant (GZ), the Israel Science Foundation-Canada programme (2633/17, VK), Sagol Institute for Longevity Research, QuinQuin Foundation, Rising Tide Foundation and Thompson Family Foundation (VK) and the European Research Council under the European Union's FP7 and H2020 (309688 and 856487, VK). Funding Information: Funding This study was supported by donations from Barbara R. Newman in memory of Daniel Newman (GZ), Brenda B. Johnston in memory of Theodore A. Johnston (GZ), and grants from the Israel Science Foundation (1009/13, IB-P), the Israel Science Foundation Morasha programme (1245/16, IB-P.), the Israel Science Foundation-Broad Institute programme (2621/18, IB-P.), the Chief Scientist of the Israel Ministry of Health (3–15017, IB-P), the Alex U. Soyka Programme (IB-P and YD) the Israel Cancer Research Fund (ICRF) Project Grant (GZ), the Israel Science Foundation-Canada programme (2633/17, VK), Sagol Institute for Longevity Research, QuinQuin Foundation, Rising Tide Foundation and Thompson Family Foundation (VK) and the European Research Council under the European Union’s FP7 and H2020 (309688 and 856487, VK). Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - Objective Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. Design To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. Results We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. Conclusions These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

AB - Objective Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. Design To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. Results We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. Conclusions These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

KW - Adenocarcinoma/metabolism

KW - Animals

KW - Cellular Senescence/drug effects

KW - Cyclooxygenase 2/metabolism

KW - Disease Models, Animal

KW - Mice

KW - Pancreatic Neoplasms/metabolism

KW - Precancerous Conditions/metabolism

KW - Senotherapeutics/therapeutic use

UR - http://www.scopus.com/inward/record.url?scp=85101874332&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2020-321112

DO - 10.1136/gutjnl-2020-321112

M3 - Article

C2 - 33649045

AN - SCOPUS:85101874332

SN - 0017-5749

VL - 71

SP - 345

EP - 355

JO - Gut

JF - Gut

IS - 2

ER -

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

Abstract

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Keywords

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