Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

Kirsi Ketola; Heidi Kaljunen; Sinja Taavitsainen; Roosa Kaarijärvi; Emmi Järvelä; Bernardo Rodríguez-Martín; Kerstin Haase; Dan J. Woodcock; Jose Tubio; David C. Wedge; Matti Nykter; G. Steven Bova

doi:10.1158/0008-5472.CAN-21-0371

Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

Kirsi Ketola^*
, Heidi Kaljunen
, Sinja Taavitsainen
, Roosa Kaarijärvi
, Emmi Järvelä
, Bernardo Rodríguez-Martín
, Kerstin Haase
, Dan J. Woodcock
, Jose Tubio
, David C. Wedge
, Matti Nykter
, G. Steven Bova

^*Corresponding author for this work

TAYS Cancer Centre

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

13 Citations (Scopus)

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Abstract

Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair–related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.

Original language	English
Pages (from-to)	4901-4909
Number of pages	9
Journal	Cancer Research
Volume	81
Issue number	19
DOIs	https://doi.org/10.1158/0008-5472.CAN-21-0371
Publication status	Published - 2021
Publication type	A1 Journal article-refereed

Funding

The authors thank A34 and his family for participating in the PELICAN (Project to ELIminate lethal CANcer) integrated clinical-molecular autopsy study of prostate cancer. They thank M. A. Eisenberger, M. A. Carducci, V. Sinibaldi, T. B. Smyth, and G. J. Mamo for oncologic and urologic clinical support; W.B. Isaacs, P. Martikainen, R. Kylatie, M. Pirinen, H. Kallio, A. Koskenalho, J. Silander, G. Hutchins, and B. Crain for study support; LuCaP 77 and 105 xenograft tissue samples analyzed were generously provided by Robert L. Vessella (University of Washington Department of Urology). Computation was supported by Tampere University, Tampere, Finland, CSC Finland, and the Finnish Institute for Molecular Medicine, Helsinki, Finland. This work was carried out with the support of UEF Cell and Tissue Imaging Unit, University of Eastern Finland, Finland and Biocenter Finland. The study was financially supported by Cancer Society of Finland (2013-present); Sigrid Juselius Foundation (2016-present); Finnish Cultural Foundation (2020-present); The Academy of Finland (2011-present); Cancer Research UK (2011?2014), PELICAN Autopsy Study family members and friends (1998?2004); John and Kathe Dyson (2000); US National Cancer Institute CA92234 (2000?2005); American Cancer Society (1998?2000); Johns Hopkins University Department of Pathology (1997?2011); Women?s Board of Johns Hopkins Hospital (1998); The Grove Foundation (1998); Association for the Cure of Cancer of the Prostate (1994?1998); Brady Urological Institute (1991?1998), American Foundation for Urologic Disease (1991?1994). The authors thank A34 and his family for participating in the PELICAN (Project to ELIminate lethal CANcer) integrated clinical-molecular autopsy study of prostate cancer. They thank M. A. Eisenberger, M. A. Carducci, V. Sinibaldi, T. B. Smyth, and G. J. Mamo for oncologic and urologic clinical support; W.B. Isaacs, P. Martikainen, R. Kylatie, M. Pirinen, H. Kallio, A. Koskenalho, J. Silander, G. Hutchins, and B. Crain for study support; LuCaP 77 and 105 xenograft tissue samples analyzed were generously provided by Robert L. Vessella (University of Washington Department of Urology). Computation was supported by Tampere University, Tampere, Finland, CSC Finland, and the Finnish Institute for Molecular Medicine, Helsinki, Finland. This work was carried out with the support of UEF Cell and Tissue Imaging Unit, University of Eastern Finland, Finland and Biocenter Finland. The study was financially supported by Cancer Society of Finland (2013-present); Sigrid Jusélius Foundation (2016-present); Finnish Cultural Foundation (2020-present); The Academy of Finland (2011-present); Cancer Research UK K. Ketola reports grants from Academy of Finland, Sigrid Jusélius Foundation, and grants from Cancer Society of Finland during the conduct of the study. S. Taavitsainen reports grants from Finnish Cultural Foundation during the conduct of the study. R. Kaarij€arvi reports grants from Finnish Cultural Foundation during the conduct of the study. M. Nykter reports grants from Cancer Society of Finland, Sigrid Jusélius Foundation, Academy of Finland, Jane And Aatos Erkko Foundation, Finnish Cancer Institute, and grants from Tampere University Hospital during the conduct of the study; grants from EU Horizon 2020 and Business Finland outside the submitted work; in addition, M. Nykter has a patent for Differential Subclone Eradication and Resistance Analysis pending. G.S. Bova reports grants from Cancer Society of Finland, Sigrid Jusélius Foundation, Finnish Cultural Foundation, and grants from Academy of Finland during the conduct of the study; in addition, G.S. Bova has a patent for Differential Subclone Eradication and Resistance Analysis pending. No disclosures were reported by the other authors.

UN SDGs

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

SDG 3 Good Health and Well-being

Publication forum classification

Publication forum level 2

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1158/0008-5472.CAN-21-0371

4901.fullFinal published version, 9.78 MBLicence: CC BY-NC-ND

https://urn.fi/URN:NBN:fi:tuni-202111028081Licence: CC BY-NC-ND

Cite this

Ketola, K., Kaljunen, H., Taavitsainen, S., Kaarijärvi, R., Järvelä, E., Rodríguez-Martín, B., Haase, K., Woodcock, D. J., Tubio, J., Wedge, D. C., Nykter, M., & Steven Bova, G. (2021). Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity. Cancer Research, 81(19), 4901-4909. https://doi.org/10.1158/0008-5472.CAN-21-0371

@article{65f8557bcae84c91a9fa7a93261886be,

title = "Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity",

abstract = "Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair–related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.",

author = "Kirsi Ketola and Heidi Kaljunen and Sinja Taavitsainen and Roosa Kaarij{\"a}rvi and Emmi J{\"a}rvel{\"a} and Bernardo Rodr{\'i}guez-Mart{\'i}n and Kerstin Haase and Woodcock, \{Dan J.\} and Jose Tubio and Wedge, \{David C.\} and Matti Nykter and \{Steven Bova\}, G.",

note = "Funding Information: The authors thank A34 and his family for participating in the PELICAN (Project to ELIminate lethal CANcer) integrated clinical-molecular autopsy study of prostate cancer. They thank M. A. Eisenberger, M. A. Carducci, V. Sinibaldi, T. B. Smyth, and G. J. Mamo for oncologic and urologic clinical support; W.B. Isaacs, P. Martikainen, R. Kylatie, M. Pirinen, H. Kallio, A. Koskenalho, J. Silander, G. Hutchins, and B. Crain for study support; LuCaP 77 and 105 xenograft tissue samples analyzed were generously provided by Robert L. Vessella (University of Washington Department of Urology). Computation was supported by Tampere University, Tampere, Finland, CSC Finland, and the Finnish Institute for Molecular Medicine, Helsinki, Finland. This work was carried out with the support of UEF Cell and Tissue Imaging Unit, University of Eastern Finland, Finland and Biocenter Finland. The study was financially supported by Cancer Society of Finland (2013-present); Sigrid Juselius Foundation (2016-present); Finnish Cultural Foundation (2020-present); The Academy of Finland (2011-present); Cancer Research UK (2011?2014), PELICAN Autopsy Study family members and friends (1998?2004); John and Kathe Dyson (2000); US National Cancer Institute CA92234 (2000?2005); American Cancer Society (1998?2000); Johns Hopkins University Department of Pathology (1997?2011); Women?s Board of Johns Hopkins Hospital (1998); The Grove Foundation (1998); Association for the Cure of Cancer of the Prostate (1994?1998); Brady Urological Institute (1991?1998), American Foundation for Urologic Disease (1991?1994). Funding Information: The authors thank A34 and his family for participating in the PELICAN (Project to ELIminate lethal CANcer) integrated clinical-molecular autopsy study of prostate cancer. They thank M. A. Eisenberger, M. A. Carducci, V. Sinibaldi, T. B. Smyth, and G. J. Mamo for oncologic and urologic clinical support; W.B. Isaacs, P. Martikainen, R. Kylatie, M. Pirinen, H. Kallio, A. Koskenalho, J. Silander, G. Hutchins, and B. Crain for study support; LuCaP 77 and 105 xenograft tissue samples analyzed were generously provided by Robert L. Vessella (University of Washington Department of Urology). Computation was supported by Tampere University, Tampere, Finland, CSC Finland, and the Finnish Institute for Molecular Medicine, Helsinki, Finland. This work was carried out with the support of UEF Cell and Tissue Imaging Unit, University of Eastern Finland, Finland and Biocenter Finland. The study was financially supported by Cancer Society of Finland (2013-present); Sigrid Jus{\'e}lius Foundation (2016-present); Finnish Cultural Foundation (2020-present); The Academy of Finland (2011-present); Cancer Research UK Funding Information: K. Ketola reports grants from Academy of Finland, Sigrid Jus{\'e}lius Foundation, and grants from Cancer Society of Finland during the conduct of the study. S. Taavitsainen reports grants from Finnish Cultural Foundation during the conduct of the study. R. Kaarij€arvi reports grants from Finnish Cultural Foundation during the conduct of the study. M. Nykter reports grants from Cancer Society of Finland, Sigrid Jus{\'e}lius Foundation, Academy of Finland, Jane And Aatos Erkko Foundation, Finnish Cancer Institute, and grants from Tampere University Hospital during the conduct of the study; grants from EU Horizon 2020 and Business Finland outside the submitted work; in addition, M. Nykter has a patent for Differential Subclone Eradication and Resistance Analysis pending. G.S. Bova reports grants from Cancer Society of Finland, Sigrid Jus{\'e}lius Foundation, Finnish Cultural Foundation, and grants from Academy of Finland during the conduct of the study; in addition, G.S. Bova has a patent for Differential Subclone Eradication and Resistance Analysis pending. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 The Authors; Published by the American Association for Cancer Research",

year = "2021",

doi = "10.1158/0008-5472.CAN-21-0371",

language = "English",

volume = "81",

pages = "4901--4909",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "19",

}

Ketola, K, Kaljunen, H, Taavitsainen, S, Kaarijärvi, R, Järvelä, E, Rodríguez-Martín, B, Haase, K, Woodcock, DJ, Tubio, J, Wedge, DC, Nykter, M & Steven Bova, G 2021, 'Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity', Cancer Research, vol. 81, no. 19, pp. 4901-4909. https://doi.org/10.1158/0008-5472.CAN-21-0371

TY - JOUR

T1 - Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

AU - Ketola, Kirsi

AU - Kaljunen, Heidi

AU - Taavitsainen, Sinja

AU - Kaarijärvi, Roosa

AU - Järvelä, Emmi

AU - Rodríguez-Martín, Bernardo

AU - Haase, Kerstin

AU - Woodcock, Dan J.

AU - Tubio, Jose

AU - Wedge, David C.

AU - Nykter, Matti

AU - Steven Bova, G.

N1 - Funding Information: The authors thank A34 and his family for participating in the PELICAN (Project to ELIminate lethal CANcer) integrated clinical-molecular autopsy study of prostate cancer. They thank M. A. Eisenberger, M. A. Carducci, V. Sinibaldi, T. B. Smyth, and G. J. Mamo for oncologic and urologic clinical support; W.B. Isaacs, P. Martikainen, R. Kylatie, M. Pirinen, H. Kallio, A. Koskenalho, J. Silander, G. Hutchins, and B. Crain for study support; LuCaP 77 and 105 xenograft tissue samples analyzed were generously provided by Robert L. Vessella (University of Washington Department of Urology). Computation was supported by Tampere University, Tampere, Finland, CSC Finland, and the Finnish Institute for Molecular Medicine, Helsinki, Finland. This work was carried out with the support of UEF Cell and Tissue Imaging Unit, University of Eastern Finland, Finland and Biocenter Finland. The study was financially supported by Cancer Society of Finland (2013-present); Sigrid Juselius Foundation (2016-present); Finnish Cultural Foundation (2020-present); The Academy of Finland (2011-present); Cancer Research UK (2011?2014), PELICAN Autopsy Study family members and friends (1998?2004); John and Kathe Dyson (2000); US National Cancer Institute CA92234 (2000?2005); American Cancer Society (1998?2000); Johns Hopkins University Department of Pathology (1997?2011); Women?s Board of Johns Hopkins Hospital (1998); The Grove Foundation (1998); Association for the Cure of Cancer of the Prostate (1994?1998); Brady Urological Institute (1991?1998), American Foundation for Urologic Disease (1991?1994). Funding Information: The authors thank A34 and his family for participating in the PELICAN (Project to ELIminate lethal CANcer) integrated clinical-molecular autopsy study of prostate cancer. They thank M. A. Eisenberger, M. A. Carducci, V. Sinibaldi, T. B. Smyth, and G. J. Mamo for oncologic and urologic clinical support; W.B. Isaacs, P. Martikainen, R. Kylatie, M. Pirinen, H. Kallio, A. Koskenalho, J. Silander, G. Hutchins, and B. Crain for study support; LuCaP 77 and 105 xenograft tissue samples analyzed were generously provided by Robert L. Vessella (University of Washington Department of Urology). Computation was supported by Tampere University, Tampere, Finland, CSC Finland, and the Finnish Institute for Molecular Medicine, Helsinki, Finland. This work was carried out with the support of UEF Cell and Tissue Imaging Unit, University of Eastern Finland, Finland and Biocenter Finland. The study was financially supported by Cancer Society of Finland (2013-present); Sigrid Jusélius Foundation (2016-present); Finnish Cultural Foundation (2020-present); The Academy of Finland (2011-present); Cancer Research UK Funding Information: K. Ketola reports grants from Academy of Finland, Sigrid Jusélius Foundation, and grants from Cancer Society of Finland during the conduct of the study. S. Taavitsainen reports grants from Finnish Cultural Foundation during the conduct of the study. R. Kaarij€arvi reports grants from Finnish Cultural Foundation during the conduct of the study. M. Nykter reports grants from Cancer Society of Finland, Sigrid Jusélius Foundation, Academy of Finland, Jane And Aatos Erkko Foundation, Finnish Cancer Institute, and grants from Tampere University Hospital during the conduct of the study; grants from EU Horizon 2020 and Business Finland outside the submitted work; in addition, M. Nykter has a patent for Differential Subclone Eradication and Resistance Analysis pending. G.S. Bova reports grants from Cancer Society of Finland, Sigrid Jusélius Foundation, Finnish Cultural Foundation, and grants from Academy of Finland during the conduct of the study; in addition, G.S. Bova has a patent for Differential Subclone Eradication and Resistance Analysis pending. No disclosures were reported by the other authors. Publisher Copyright: © 2021 The Authors; Published by the American Association for Cancer Research

PY - 2021

Y1 - 2021

N2 - Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair–related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.

AB - Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair–related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.

U2 - 10.1158/0008-5472.CAN-21-0371

DO - 10.1158/0008-5472.CAN-21-0371

M3 - Article

C2 - 34348967

AN - SCOPUS:85117051512

SN - 0008-5472

VL - 81

SP - 4901

EP - 4909

JO - Cancer Research

JF - Cancer Research

IS - 19

ER -

Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

Abstract

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