Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling

Inma M Berenjeno; Roberto Piñeiro; Sandra D Castillo; Wayne Pearce; Nicholas McGranahan; Sally M Dewhurst; Valerie Meniel; Nicolai J Birkbak; Evelyn Lau; Laurent Sansregret; Daniele Morelli; Nnennaya Kanu; Shankar Srinivas; Mariona Graupera; Victoria E R Parker; Karen G Montgomery; Larissa S Moniz; Cheryl L Scudamore; Wayne A Phillips; Robert K Semple; Alan Clarke; Charles Swanton; Bart Vanhaesebroeck

doi:10.1038/s41467-017-02002-4

Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling

Inma M Berenjeno, Roberto Piñeiro, Sandra D Castillo, Wayne Pearce, Nicholas McGranahan, Sally M Dewhurst, Valerie Meniel, Nicolai J Birkbak, Evelyn Lau, Laurent Sansregret, Daniele Morelli, Nnennaya Kanu, Shankar Srinivas, Mariona Graupera, Victoria E R Parker, Karen G Montgomery, Larissa S Moniz, Cheryl L Scudamore, Wayne A Phillips, Robert K SempleAlan Clarke, Charles Swanton, Bart Vanhaesebroeck

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Abstract / Description of output

Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.

Original language	English
Pages (from-to)	1773
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02002-4
Publication status	Published - 24 Nov 2017

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10.1038/s41467-017-02002-4

s41467-017-02002-4
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Berenjeno, I. M., Piñeiro, R., Castillo, S. D., Pearce, W., McGranahan, N., Dewhurst, S. M., Meniel, V., Birkbak, N. J., Lau, E., Sansregret, L., Morelli, D., Kanu, N., Srinivas, S., Graupera, M., Parker, V. E. R., Montgomery, K. G., Moniz, L. S., Scudamore, C. L., Phillips, W. A., ... Vanhaesebroeck, B. (2017). Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling. Nature Communications, 8(1), 1773. https://doi.org/10.1038/s41467-017-02002-4

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abstract = "Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.",

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year = "2017",

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doi = "10.1038/s41467-017-02002-4",

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Berenjeno, IM, Piñeiro, R, Castillo, SD, Pearce, W, McGranahan, N, Dewhurst, SM, Meniel, V, Birkbak, NJ, Lau, E, Sansregret, L, Morelli, D, Kanu, N, Srinivas, S, Graupera, M, Parker, VER, Montgomery, KG, Moniz, LS, Scudamore, CL, Phillips, WA, Semple, RK, Clarke, A, Swanton, C & Vanhaesebroeck, B 2017, 'Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling', Nature Communications, vol. 8, no. 1, pp. 1773. https://doi.org/10.1038/s41467-017-02002-4

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T1 - Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling

AU - Berenjeno, Inma M

AU - Piñeiro, Roberto

AU - Castillo, Sandra D

AU - Pearce, Wayne

AU - McGranahan, Nicholas

AU - Dewhurst, Sally M

AU - Meniel, Valerie

AU - Birkbak, Nicolai J

AU - Lau, Evelyn

AU - Sansregret, Laurent

AU - Morelli, Daniele

AU - Kanu, Nnennaya

AU - Srinivas, Shankar

AU - Graupera, Mariona

AU - Parker, Victoria E R

AU - Montgomery, Karen G

AU - Moniz, Larissa S

AU - Scudamore, Cheryl L

AU - Phillips, Wayne A

AU - Semple, Robert K

AU - Clarke, Alan

AU - Swanton, Charles

AU - Vanhaesebroeck, Bart

PY - 2017/11/24

Y1 - 2017/11/24

N2 - Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.

AB - Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.

KW - Journal Article

U2 - 10.1038/s41467-017-02002-4

DO - 10.1038/s41467-017-02002-4

M3 - Article

C2 - 29170395

SN - 2041-1723

VL - 8

SP - 1773

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling

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