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Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones

Author

Listed:
  • Maja Marklund

    (Science for Life Laboratory)

  • Niklas Schultz

    (Karolinska Institute, Science for Life Laboratory)

  • Stefanie Friedrich

    (Stockholm University, Science for Laboratory)

  • Emelie Berglund

    (Science for Life Laboratory)

  • Firas Tarish

    (Karolinska Institute, Science for Life Laboratory)

  • Anna Tanoglidi

    (Evangelismos General Hospital)

  • Yao Liu

    (Karolinska Institute, Science for Life Laboratory)

  • Ludvig Bergenstråhle

    (Science for Life Laboratory)

  • Andrew Erickson

    (University of Oxford)

  • Thomas Helleday

    (Karolinska Institute, Science for Life Laboratory)

  • Alastair D. Lamb

    (University of Oxford)

  • Erik Sonnhammer

    (Stockholm University, Science for Laboratory)

  • Joakim Lundeberg

    (Science for Life Laboratory)

Abstract

The molecular mechanisms underlying lethal castration-resistant prostate cancer remain poorly understood, with intratumoral heterogeneity a likely contributing factor. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in needle biopsies collected before and after treatment with androgen deprivation therapy. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome-wide data. Our data-driven analysis of transcriptomes identifies several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Certain cell populations present before treatment exhibit gene expression profiles that match those of resistant tumor cell clusters, present after treatment. We confirm that these clusters are resistant by the localization of active androgen receptors to the nuclei in cancer cells post-treatment. Our data also demonstrates that most stromal cells adjacent to resistant clusters do not express the androgen receptor, and we identify differentially expressed genes for these cells. Altogether, this study shows the potential to increase the power in predicting resistant tumors.

Suggested Citation

  • Maja Marklund & Niklas Schultz & Stefanie Friedrich & Emelie Berglund & Firas Tarish & Anna Tanoglidi & Yao Liu & Ludvig Bergenstråhle & Andrew Erickson & Thomas Helleday & Alastair D. Lamb & Erik Son, 2022. "Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33069-3
    DOI: 10.1038/s41467-022-33069-3
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    References listed on IDEAS

    as
    1. Emelie Berglund & Jonas Maaskola & Niklas Schultz & Stefanie Friedrich & Maja Marklund & Joseph Bergenstråhle & Firas Tarish & Anna Tanoglidi & Sanja Vickovic & Ludvig Larsson & Fredrik Salmén & Chri, 2018. "Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    2. Andrew Erickson & Mengxiao He & Emelie Berglund & Maja Marklund & Reza Mirzazadeh & Niklas Schultz & Linda Kvastad & Alma Andersson & Ludvig Bergenstråhle & Joseph Bergenstråhle & Ludvig Larsson & Lei, 2022. "Spatially resolved clonal copy number alterations in benign and malignant tissue," Nature, Nature, vol. 608(7922), pages 360-367, August.
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