Partitioning of cancer therapeutics in nuclear condensates

Isaac A. Klein; Ann Boija; Lena K. Afeyan; Susana Wilson Hawken; Mengyang Fan; Alessandra Dall'Agnese; Ozgur Oksuz; Jonathan E. Henninger; Krishna Shrinivas; Benjamin R. Sabari; Ido Sagi; Victoria E. Clark; Jesse M. Platt; Mrityunjoy Kar; Patrick M. McCall; Alicia V. Zamudio; John C. Manteiga; Eliot L. Coffey; Charles H. Li; Nancy M. Hannett; Yang Eric Guo; Tim Michael Decker; Tong Ihn Lee; Tinghu Zhang; Jing Ke Weng; Dylan J. Taatjes; Arup Chakraborty; Phillip A. Sharp; Young Tae Chang; Anthony A. Hyman; Nathanael S. Gray; Richard A. Young

doi:10.1126/science.aaz4427

Partitioning of cancer therapeutics in nuclear condensates

Isaac A. Klein, Ann Boija, Lena K. Afeyan, Susana Wilson Hawken, Mengyang Fan, Alessandra Dall'Agnese, Ozgur Oksuz, Jonathan E. Henninger, Krishna Shrinivas, Benjamin R. Sabari, Ido Sagi, Victoria E. Clark, Jesse M. Platt, Mrityunjoy Kar, Patrick M. McCall, Alicia V. Zamudio, John C. Manteiga, Eliot L. Coffey, Charles H. Li, Nancy M. HannettYang Eric Guo, Tim Michael Decker, Tong Ihn Lee, Tinghu Zhang, Jing Ke Weng, Dylan J. Taatjes, Arup Chakraborty, Phillip A. Sharp, Young Tae Chang, Anthony A. Hyman, Nathanael S. Gray, Richard A. Young

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

322 Scopus citations

Abstract

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

Original language	English
Pages (from-to)	1386-1392
Number of pages	7
Journal	Science
Volume	368
Issue number	6497
DOIs	https://doi.org/10.1126/science.aaz4427
State	Published - 19 Jun 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Funding

We thank C. Glinkerman for helpful comments; W. Salmon of the W.M Keck Microscopy Facility and T. Volkert, J. Love, S. Mraz, and S. Gupta of the Whitehead Genome Technologies Core for technical assistance; and staff of the light microscopy facility at the MPI-CBG in Dresden for extensive help and support. This work was supported by NIH grants GM123511, CA213333, and CA155258 (R.A.Y.), NSF grant PHY1743900 (R.A.Y.), funds from Novo Nordisk (R.A.Y. and P.A.S.) NIH grant GM117370 (D.J.T.), Max Planck Society (A.A.H.), American Society of Clinical Oncology Young Investigator Award (I.A.K.), American Cancer Society Postdoctoral Fellowship (I.A.K.), Ovarian Cancer Research Alliance Mentored Investigator Award (I.A.K.), Swedish Research Council Postdoctoral Fellowship (VR 2017-00372) (A.B.), Hope Funds for Cancer Research (AD), Gruss-Lipper Postdoctoral Fellowship and by the Rothschild Postdoctoral Fellowship (I.S.), NIH grant T32:5T32DK007191-45 (J.M.P.), German Research Foundation DFG postdoctoral fellowship DE 3069/1-1 (T.-M.D.), Cancer Research Institute Irvington Fellowship (Y.E.G.), Damon Runyon Cancer Research Foundation Fellowship (2309-17) (BRS), ELBE postdoctoral fellowship (P.M.).

Funders	Funder number
ELBE
National Science Foundation	PHY1743900
National Institutes of Health	GM123511, CA155258, CA213333
American Cancer Society
National Institute of General Medical Sciences	R01GM034277
Cancer research institute
Damon Runyon Cancer Research Foundation	2309-17
American Society of Clinical Oncology
Hope Funds for Cancer Research	T32:5T32DK007191-45
Ovarian Cancer Research Alliance
Deutsche Forschungsgemeinschaft	DE 3069/1-1
Max-Planck-Gesellschaft
Novo Nordisk	GM117370
Vetenskapsrådet	VR 2017-00372

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/science.aaz4427

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Klein, I. A., Boija, A., Afeyan, L. K., Hawken, S. W., Fan, M., Dall'Agnese, A., Oksuz, O., Henninger, J. E., Shrinivas, K., Sabari, B. R., Sagi, I., Clark, V. E., Platt, J. M., Kar, M., McCall, P. M., Zamudio, A. V., Manteiga, J. C., Coffey, E. L., Li, C. H., ... Young, R. A. (2020). Partitioning of cancer therapeutics in nuclear condensates. Science, 368(6497), 1386-1392. https://doi.org/10.1126/science.aaz4427

@article{bca79c21c8714994a89a3a776b34fe80,

title = "Partitioning of cancer therapeutics in nuclear condensates",

abstract = "The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.",

author = "Klein, {Isaac A.} and Ann Boija and Afeyan, {Lena K.} and Hawken, {Susana Wilson} and Mengyang Fan and Alessandra Dall'Agnese and Ozgur Oksuz and Henninger, {Jonathan E.} and Krishna Shrinivas and Sabari, {Benjamin R.} and Ido Sagi and Clark, {Victoria E.} and Platt, {Jesse M.} and Mrityunjoy Kar and McCall, {Patrick M.} and Zamudio, {Alicia V.} and Manteiga, {John C.} and Coffey, {Eliot L.} and Li, {Charles H.} and Hannett, {Nancy M.} and Guo, {Yang Eric} and Decker, {Tim Michael} and Lee, {Tong Ihn} and Tinghu Zhang and Weng, {Jing Ke} and Taatjes, {Dylan J.} and Arup Chakraborty and Sharp, {Phillip A.} and Chang, {Young Tae} and Hyman, {Anthony A.} and Gray, {Nathanael S.} and Young, {Richard A.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2020",

month = jun,

day = "19",

doi = "10.1126/science.aaz4427",

language = "אנגלית",

volume = "368",

pages = "1386--1392",

journal = "Science",

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publisher = "American Association for the Advancement of Science",

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Klein, IA, Boija, A, Afeyan, LK, Hawken, SW, Fan, M, Dall'Agnese, A, Oksuz, O, Henninger, JE, Shrinivas, K, Sabari, BR, Sagi, I, Clark, VE, Platt, JM, Kar, M, McCall, PM, Zamudio, AV, Manteiga, JC, Coffey, EL, Li, CH, Hannett, NM, Guo, YE, Decker, TM, Lee, TI, Zhang, T, Weng, JK, Taatjes, DJ, Chakraborty, A, Sharp, PA, Chang, YT, Hyman, AA, Gray, NS & Young, RA 2020, 'Partitioning of cancer therapeutics in nuclear condensates', Science, vol. 368, no. 6497, pp. 1386-1392. https://doi.org/10.1126/science.aaz4427

TY - JOUR

T1 - Partitioning of cancer therapeutics in nuclear condensates

AU - Klein, Isaac A.

AU - Boija, Ann

AU - Afeyan, Lena K.

AU - Hawken, Susana Wilson

AU - Fan, Mengyang

AU - Dall'Agnese, Alessandra

AU - Oksuz, Ozgur

AU - Henninger, Jonathan E.

AU - Shrinivas, Krishna

AU - Sabari, Benjamin R.

AU - Sagi, Ido

AU - Clark, Victoria E.

AU - Platt, Jesse M.

AU - Kar, Mrityunjoy

AU - McCall, Patrick M.

AU - Zamudio, Alicia V.

AU - Manteiga, John C.

AU - Coffey, Eliot L.

AU - Li, Charles H.

AU - Hannett, Nancy M.

AU - Guo, Yang Eric

AU - Decker, Tim Michael

AU - Lee, Tong Ihn

AU - Zhang, Tinghu

AU - Weng, Jing Ke

AU - Taatjes, Dylan J.

AU - Chakraborty, Arup

AU - Sharp, Phillip A.

AU - Chang, Young Tae

AU - Hyman, Anthony A.

AU - Gray, Nathanael S.

AU - Young, Richard A.

PY - 2020/6/19

Y1 - 2020/6/19

N2 - The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

AB - The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

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AN - SCOPUS:85086725637

SN - 0036-8075

VL - 368

SP - 1386

EP - 1392

JO - Science

JF - Science

IS - 6497

ER -

Partitioning of cancer therapeutics in nuclear condensates

Abstract

Bibliographical note

Funding

UN SDGs

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