Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy

Marie Eve Wedge; Victoria A. Jennings; Mathieu J.F. Crupi; Joanna Poutou; Taylor Jamieson; Adrian Pelin; Giuseppe Pugliese; Christiano Tanese de Souza; Julia Petryk; Brian J. Laight; Meaghan Boileau; Zaid Taha; Nouf Alluqmani; Hayley E. McKay; Larissa Pikor; Sarwat Tahsin Khan; Taha Azad; Reza Rezaei; Bradley Austin; Xiaohong He; David Mansfield; Elaine Rose; Emily E.F. Brown; Natalie Crawford; Almohanad Alkayyal; Abera Surendran; Ragunath Singaravelu; Dominic G. Roy; Gemma Migneco; Benjamin McSweeney; Mary Lynn Cottee; Egon J. Jacobus; Brian A. Keller; Takafumi N. Yamaguchi; Paul C. Boutros; Michele Geoffrion; Katey J. Rayner; Avijit Chatterjee; Rebecca C. Auer; Jean Simon Diallo; Derrick Gibbings; Benjamin R. tenOever; Alan Melcher; John C. Bell; Carolina S. Ilkow

doi:10.1038/s41467-022-29526-8

Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy

Marie Eve Wedge, Victoria A. Jennings, Mathieu J.F. Crupi, Joanna Poutou, Taylor Jamieson, Adrian Pelin, Giuseppe Pugliese, Christiano Tanese de Souza, Julia Petryk, Brian J. Laight, Meaghan Boileau, Zaid Taha, Nouf Alluqmani, Hayley E. McKay, Larissa Pikor, Sarwat Tahsin Khan, Taha Azad, Reza Rezaei, Bradley Austin, Xiaohong HeDavid Mansfield, Elaine Rose, Emily E.F. Brown, Natalie Crawford, Almohanad Alkayyal, Abera Surendran, Ragunath Singaravelu, Dominic G. Roy, Gemma Migneco, Benjamin McSweeney, Mary Lynn Cottee, Egon J. Jacobus, Brian A. Keller, Takafumi N. Yamaguchi, Paul C. Boutros, Michele Geoffrion, Katey J. Rayner, Avijit Chatterjee, Rebecca C. Auer, Jean Simon Diallo, Derrick Gibbings, Benjamin R. tenOever, Alan Melcher, John C. Bell, Carolina S. Ilkow

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

34 Scopus citations

Abstract

Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or “cancer-killing” viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.

Original language	English
Article number	1898
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-29526-8
State	Published - Dec 2022

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Wedge, M. E., Jennings, V. A., Crupi, M. J. F., Poutou, J., Jamieson, T., Pelin, A., Pugliese, G., de Souza, C. T., Petryk, J., Laight, B. J., Boileau, M., Taha, Z., Alluqmani, N., McKay, H. E., Pikor, L., Khan, S. T., Azad, T., Rezaei, R., Austin, B., ... Ilkow, C. S. (2022). Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy. Nature Communications, 13(1), Article 1898. https://doi.org/10.1038/s41467-022-29526-8

@article{db7602c683b14bc9b1ecefe1db717cb4,

title = "Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy",

abstract = "Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or “cancer-killing” viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.",

author = "Wedge, {Marie Eve} and Jennings, {Victoria A.} and Crupi, {Mathieu J.F.} and Joanna Poutou and Taylor Jamieson and Adrian Pelin and Giuseppe Pugliese and {de Souza}, {Christiano Tanese} and Julia Petryk and Laight, {Brian J.} and Meaghan Boileau and Zaid Taha and Nouf Alluqmani and McKay, {Hayley E.} and Larissa Pikor and Khan, {Sarwat Tahsin} and Taha Azad and Reza Rezaei and Bradley Austin and Xiaohong He and David Mansfield and Elaine Rose and Brown, {Emily E.F.} and Natalie Crawford and Almohanad Alkayyal and Abera Surendran and Ragunath Singaravelu and Roy, {Dominic G.} and Gemma Migneco and Benjamin McSweeney and Cottee, {Mary Lynn} and Jacobus, {Egon J.} and Keller, {Brian A.} and Yamaguchi, {Takafumi N.} and Boutros, {Paul C.} and Michele Geoffrion and Rayner, {Katey J.} and Avijit Chatterjee and Auer, {Rebecca C.} and Diallo, {Jean Simon} and Derrick Gibbings and tenOever, {Benjamin R.} and Alan Melcher and Bell, {John C.} and Ilkow, {Carolina S.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-29526-8",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Wedge, ME, Jennings, VA, Crupi, MJF, Poutou, J, Jamieson, T, Pelin, A, Pugliese, G, de Souza, CT, Petryk, J, Laight, BJ, Boileau, M, Taha, Z, Alluqmani, N, McKay, HE, Pikor, L, Khan, ST, Azad, T, Rezaei, R, Austin, B, He, X, Mansfield, D, Rose, E, Brown, EEF, Crawford, N, Alkayyal, A, Surendran, A, Singaravelu, R, Roy, DG, Migneco, G, McSweeney, B, Cottee, ML, Jacobus, EJ, Keller, BA, Yamaguchi, TN, Boutros, PC, Geoffrion, M, Rayner, KJ, Chatterjee, A, Auer, RC, Diallo, JS, Gibbings, D, tenOever, BR, Melcher, A, Bell, JC & Ilkow, CS 2022, 'Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy', Nature Communications, vol. 13, no. 1, 1898. https://doi.org/10.1038/s41467-022-29526-8

TY - JOUR

T1 - Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy

AU - Wedge, Marie Eve

AU - Jennings, Victoria A.

AU - Crupi, Mathieu J.F.

AU - Poutou, Joanna

AU - Jamieson, Taylor

AU - Pelin, Adrian

AU - Pugliese, Giuseppe

AU - de Souza, Christiano Tanese

AU - Petryk, Julia

AU - Laight, Brian J.

AU - Boileau, Meaghan

AU - Taha, Zaid

AU - Alluqmani, Nouf

AU - McKay, Hayley E.

AU - Pikor, Larissa

AU - Khan, Sarwat Tahsin

AU - Azad, Taha

AU - Rezaei, Reza

AU - Austin, Bradley

AU - He, Xiaohong

AU - Mansfield, David

AU - Rose, Elaine

AU - Brown, Emily E.F.

AU - Crawford, Natalie

AU - Alkayyal, Almohanad

AU - Surendran, Abera

AU - Singaravelu, Ragunath

AU - Roy, Dominic G.

AU - Migneco, Gemma

AU - McSweeney, Benjamin

AU - Cottee, Mary Lynn

AU - Jacobus, Egon J.

AU - Keller, Brian A.

AU - Yamaguchi, Takafumi N.

AU - Boutros, Paul C.

AU - Geoffrion, Michele

AU - Rayner, Katey J.

AU - Chatterjee, Avijit

AU - Auer, Rebecca C.

AU - Diallo, Jean Simon

AU - Gibbings, Derrick

AU - tenOever, Benjamin R.

AU - Melcher, Alan

AU - Bell, John C.

AU - Ilkow, Carolina S.

PY - 2022/12

Y1 - 2022/12

N2 - Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or “cancer-killing” viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.

AB - Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or “cancer-killing” viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.

UR - http://www.scopus.com/inward/record.url?scp=85127953606&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-29526-8

DO - 10.1038/s41467-022-29526-8

M3 - Article

C2 - 35393414

AN - SCOPUS:85127953606

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1898

ER -

Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy

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