Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

Joseph M. Chan; Samir Zaidi; Jillian R. Love; Jimmy L. Zhao; Manu Setty; Kristine M. Wadosky; Anuradha Gopalan; Zi Ning Choo; Sitara Persad; Jungmin Choi; Justin LaClair; Kayla E. Lawrence; Ojasvi Chaudhary; Tianhao Xu; Ignas Masilionis; Irina Linkov; Shangqian Wang; Cindy Lee; Afsar Barlas; Michael J. Morris; Linas Mazutis; Ronan Chaligne; Yu Chen; David W. Goodrich; Wouter R. Karthaus; Dana Pe'er; Charles L. Sawyers

doi:10.1126/science.abn0478

Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

Joseph M. Chan, Samir Zaidi, Jillian R. Love, Jimmy L. Zhao, Manu Setty, Kristine M. Wadosky, Anuradha Gopalan, Zi Ning Choo, Sitara Persad, Jungmin Choi, Justin LaClair, Kayla E. Lawrence, Ojasvi Chaudhary, Tianhao Xu, Ignas Masilionis, Irina Linkov, Shangqian Wang, Cindy Lee, Afsar Barlas, Michael J. MorrisLinas Mazutis, Ronan Chaligne, Yu Chen, David W. Goodrich, Wouter R. Karthaus, Dana Pe'er, Charles L. Sawyers

Department of Biomedical Sciences

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

107 Citations (Scopus)

Abstract

Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

Original language	English
Pages (from-to)	1180-1191
Number of pages	12
Journal	Science
Volume	377
Issue number	6611
DOIs	https://doi.org/10.1126/science.abn0478
Publication status	Published - 2022 Sept 9

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© 2022 American Association for the Advancement of Science. All rights reserved.

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Chan, J. M., Zaidi, S., Love, J. R., Zhao, J. L., Setty, M., Wadosky, K. M., Gopalan, A., Choo, Z. N., Persad, S., Choi, J., LaClair, J., Lawrence, K. E., Chaudhary, O., Xu, T., Masilionis, I., Linkov, I., Wang, S., Lee, C., Barlas, A., ... Sawyers, C. L. (2022). Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling. Science, 377(6611), 1180-1191. https://doi.org/10.1126/science.abn0478

Chan, JM, Zaidi, S, Love, JR, Zhao, JL, Setty, M, Wadosky, KM, Gopalan, A, Choo, ZN, Persad, S, Choi, J, LaClair, J, Lawrence, KE, Chaudhary, O, Xu, T, Masilionis, I, Linkov, I, Wang, S, Lee, C, Barlas, A, Morris, MJ, Mazutis, L, Chaligne, R, Chen, Y, Goodrich, DW, Karthaus, WR, Pe'er, D & Sawyers, CL 2022, 'Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling', Science, vol. 377, no. 6611, pp. 1180-1191. https://doi.org/10.1126/science.abn0478

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title = "Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling",

abstract = "Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.",

author = "Chan, {Joseph M.} and Samir Zaidi and Love, {Jillian R.} and Zhao, {Jimmy L.} and Manu Setty and Wadosky, {Kristine M.} and Anuradha Gopalan and Choo, {Zi Ning} and Sitara Persad and Jungmin Choi and Justin LaClair and Lawrence, {Kayla E.} and Ojasvi Chaudhary and Tianhao Xu and Ignas Masilionis and Irina Linkov and Shangqian Wang and Cindy Lee and Afsar Barlas and Morris, {Michael J.} and Linas Mazutis and Ronan Chaligne and Yu Chen and Goodrich, {David W.} and Karthaus, {Wouter R.} and Dana Pe'er and Sawyers, {Charles L.}",

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AU - Chan, Joseph M.

AU - Zaidi, Samir

AU - Love, Jillian R.

AU - Zhao, Jimmy L.

AU - Setty, Manu

AU - Wadosky, Kristine M.

AU - Gopalan, Anuradha

AU - Choo, Zi Ning

AU - Persad, Sitara

AU - Choi, Jungmin

AU - LaClair, Justin

AU - Lawrence, Kayla E.

AU - Chaudhary, Ojasvi

AU - Xu, Tianhao

AU - Masilionis, Ignas

AU - Linkov, Irina

AU - Wang, Shangqian

AU - Lee, Cindy

AU - Barlas, Afsar

AU - Morris, Michael J.

AU - Mazutis, Linas

AU - Chaligne, Ronan

AU - Chen, Yu

AU - Goodrich, David W.

AU - Karthaus, Wouter R.

AU - Pe'er, Dana

AU - Sawyers, Charles L.

PY - 2022/9/9

Y1 - 2022/9/9

N2 - Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

AB - Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

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Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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