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Integrated systems-genetic analyses reveal a network target for delaying glioma progression

Integrated systems-genetic analyses reveal a network target for delaying glioma progression
Integrated systems-genetic analyses reveal a network target for delaying glioma progression

OBJECTIVE

To identify a convergent, multitarget proliferation characteristic for astrocytoma transformation that could be targeted for therapy discovery.

METHODS

 Using an integrated functional genomics approach, we prioritized networks associated with astrocytoma progression using the following criteria: differential co-expression between grade II and grade III IDH1-mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and sample-level genomic features. Drugs targeting the identified multitarget network characteristic for astrocytoma transformation were computationally predicted using drug transcriptional perturbation data and validated using primary human astrocytoma cells.

RESULTS

 A single network, M2, consisting of 177 genes, was associated with glioma progression on the basis of the above criteria. Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysis of genome-wide gene-regulatory interactions using mutual information and DNA-protein interactions revealed the known regulators of cell cycle processes FoxM1, B-Myb, and E2F2 as key regulators of M2. These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drug target regulating astrocytoma transformation, we identified several drugs that are predicted to restore M2 expression in anaplastic astrocytoma toward its low-grade profile and of these, we validated the known antiproliferative drug resveratrol as down-regulating multiple nodes of M2 including at nanomolar concentrations achievable in human cerebrospinal fluid by oral dosing.

INTERPRETATION

 Our results identify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2-based drug screening to identify new compounds for preventing glioma transformation.

Astrocytoma/genetics, Brain Neoplasms/genetics, Cell Line, Tumor, Cell Proliferation, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Glioma/genetics, Humans, Mutation
2328-9503
1616-1638
Laaniste, Liisi
18939583-1f7b-45d8-adbe-37ea18c5974f
Srivastava, Prashant K
be70bb08-c734-40bb-8b98-32c00bf42c2c
Stylianou, Julianna
ab2dc7ed-617c-4a24-ab69-5832542d1634
Syed, Nelofer
af7f3dd2-92be-414d-8074-0a410f2fd178
Cases-Cunillera, Silvia
4502517a-aac8-4d4f-a735-53ebe14ff6b3
Shkura, Kirill
68193e9b-7c17-4526-a970-2750c95b44d2
Zeng, Qingyu
c8a92cd3-e45b-4cd4-8e2a-5ef38bae839a
Rackham, Owen J.L.
8122eb1f-6e9f-4da5-90e1-ce108ccbbcbf
Langley, Sarah R.
897e76ce-ff32-43dc-abe6-6b347bad7fd1
Delahaye-Duriez, Andree
5e38d261-462a-41a9-bee7-74d888f708e5
O'Neill, Kevin
4005ca31-17ae-485c-bd20-ea4c65e76696
Williams, Matthew
b0f899a3-e291-4085-9565-b141d79069dc
Becker, Albert
c3c62457-41b6-4372-951f-f3970b7637e8
Roncaroli, Federico
e21844d5-c482-497f-b9a0-ce5f72269d1a
Petretto, Enrico
a8a7d254-ea06-4ab3-ba7e-b653349a29f4
Johnson, Michael R.
33a0d8cb-491b-4b3f-b193-540a331ac705
Laaniste, Liisi
18939583-1f7b-45d8-adbe-37ea18c5974f
Srivastava, Prashant K
be70bb08-c734-40bb-8b98-32c00bf42c2c
Stylianou, Julianna
ab2dc7ed-617c-4a24-ab69-5832542d1634
Syed, Nelofer
af7f3dd2-92be-414d-8074-0a410f2fd178
Cases-Cunillera, Silvia
4502517a-aac8-4d4f-a735-53ebe14ff6b3
Shkura, Kirill
68193e9b-7c17-4526-a970-2750c95b44d2
Zeng, Qingyu
c8a92cd3-e45b-4cd4-8e2a-5ef38bae839a
Rackham, Owen J.L.
8122eb1f-6e9f-4da5-90e1-ce108ccbbcbf
Langley, Sarah R.
897e76ce-ff32-43dc-abe6-6b347bad7fd1
Delahaye-Duriez, Andree
5e38d261-462a-41a9-bee7-74d888f708e5
O'Neill, Kevin
4005ca31-17ae-485c-bd20-ea4c65e76696
Williams, Matthew
b0f899a3-e291-4085-9565-b141d79069dc
Becker, Albert
c3c62457-41b6-4372-951f-f3970b7637e8
Roncaroli, Federico
e21844d5-c482-497f-b9a0-ce5f72269d1a
Petretto, Enrico
a8a7d254-ea06-4ab3-ba7e-b653349a29f4
Johnson, Michael R.
33a0d8cb-491b-4b3f-b193-540a331ac705

Laaniste, Liisi, Srivastava, Prashant K, Stylianou, Julianna, Syed, Nelofer, Cases-Cunillera, Silvia, Shkura, Kirill, Zeng, Qingyu, Rackham, Owen J.L., Langley, Sarah R., Delahaye-Duriez, Andree, O'Neill, Kevin, Williams, Matthew, Becker, Albert, Roncaroli, Federico, Petretto, Enrico and Johnson, Michael R. (2019) Integrated systems-genetic analyses reveal a network target for delaying glioma progression. Annals of Clinical and Translational Neurology, 6 (9), 1616-1638. (doi:10.1002/acn3.50850).

Record type: Article

Abstract

OBJECTIVE

To identify a convergent, multitarget proliferation characteristic for astrocytoma transformation that could be targeted for therapy discovery.

METHODS

 Using an integrated functional genomics approach, we prioritized networks associated with astrocytoma progression using the following criteria: differential co-expression between grade II and grade III IDH1-mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and sample-level genomic features. Drugs targeting the identified multitarget network characteristic for astrocytoma transformation were computationally predicted using drug transcriptional perturbation data and validated using primary human astrocytoma cells.

RESULTS

 A single network, M2, consisting of 177 genes, was associated with glioma progression on the basis of the above criteria. Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysis of genome-wide gene-regulatory interactions using mutual information and DNA-protein interactions revealed the known regulators of cell cycle processes FoxM1, B-Myb, and E2F2 as key regulators of M2. These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drug target regulating astrocytoma transformation, we identified several drugs that are predicted to restore M2 expression in anaplastic astrocytoma toward its low-grade profile and of these, we validated the known antiproliferative drug resveratrol as down-regulating multiple nodes of M2 including at nanomolar concentrations achievable in human cerebrospinal fluid by oral dosing.

INTERPRETATION

 Our results identify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2-based drug screening to identify new compounds for preventing glioma transformation.

This record has no associated files available for download.

More information

e-pub ahead of print date: 17 August 2019
Published date: September 2019
Additional Information: © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
Keywords: Astrocytoma/genetics, Brain Neoplasms/genetics, Cell Line, Tumor, Cell Proliferation, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Glioma/genetics, Humans, Mutation

Identifiers

Local EPrints ID: 446818
URI: http://eprints.soton.ac.uk/id/eprint/446818
ISSN: 2328-9503
PURE UUID: 283b5b02-7322-4387-bec3-eade99b9a9b9
ORCID for Owen J.L. Rackham: ORCID iD orcid.org/0000-0002-4390-0872
ORCID for Michael R. Johnson: ORCID iD orcid.org/0000-0002-5566-6147

Catalogue record

Date deposited: 23 Feb 2021 17:32
Last modified: 30 Jun 2022 02:02

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Contributors

Author: Liisi Laaniste
Author: Prashant K Srivastava
Author: Julianna Stylianou
Author: Nelofer Syed
Author: Silvia Cases-Cunillera
Author: Kirill Shkura
Author: Qingyu Zeng
Author: Sarah R. Langley
Author: Andree Delahaye-Duriez
Author: Kevin O'Neill
Author: Matthew Williams
Author: Albert Becker
Author: Federico Roncaroli
Author: Enrico Petretto
Author: Michael R. Johnson ORCID iD

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