The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies

Zenggang Li; Andrei A. Ivanov; Rina Su; Valentina Gonzalez-Pecchi; Qi Qi; Songlin Liu; Philip Webber; Elizabeth McMillan; Lauren Rusnak; Cau Pham; Xiaoqian Chen; Xiulei Mo; Brian Revennaugh; Wei Zhou; Adam Marcus; Sahar Harati; Xiang Chen; Margaret A. Johns; Michael A. White; Carlos Moreno; Lee A D Cooper; Yuhong Du; Fadlo R. Khuri; Haian Fu

doi:10.1038/ncomms14356

The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies

Zenggang Li, Andrei A. Ivanov, Rina Su, Valentina Gonzalez-Pecchi, Qi Qi, Songlin Liu, Philip Webber, Elizabeth McMillan, Lauren Rusnak, Cau Pham, Xiaoqian Chen, Xiulei Mo, Brian Revennaugh, Wei Zhou, Adam Marcus, Sahar Harati, Xiang Chen, Margaret A. Johns, Michael A. White, Carlos MorenoLee A D Cooper, Yuhong Du, Fadlo R. Khuri, Haian Fu

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

154 Scopus citations

Abstract

As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)-MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation.

Original language	English (US)
Article number	14356
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14356
State	Published - Feb 16 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Li, Z., Ivanov, A. A., Su, R., Gonzalez-Pecchi, V., Qi, Q., Liu, S., Webber, P., McMillan, E., Rusnak, L., Pham, C., Chen, X., Mo, X., Revennaugh, B., Zhou, W., Marcus, A., Harati, S., Chen, X., Johns, M. A., White, M. A., ... Fu, H. (2017). The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies. Nature communications, 8, Article 14356. https://doi.org/10.1038/ncomms14356

Li, Z, Ivanov, AA, Su, R, Gonzalez-Pecchi, V, Qi, Q, Liu, S, Webber, P, McMillan, E, Rusnak, L, Pham, C, Chen, X, Mo, X, Revennaugh, B, Zhou, W, Marcus, A, Harati, S, Chen, X, Johns, MA, White, MA, Moreno, C, Cooper, LAD, Du, Y, Khuri, FR & Fu, H 2017, 'The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies', Nature communications, vol. 8, 14356. https://doi.org/10.1038/ncomms14356

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abstract = "As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)-MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation.",

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AU - Qi, Qi

AU - Liu, Songlin

AU - Webber, Philip

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AU - Marcus, Adam

AU - Harati, Sahar

AU - Chen, Xiang

AU - Johns, Margaret A.

AU - White, Michael A.

AU - Moreno, Carlos

AU - Cooper, Lee A D

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AU - Khuri, Fadlo R.

AU - Fu, Haian

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N2 - As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)-MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation.

AB - As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)-MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation.

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The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies

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