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

Maja Marklund, Niklas Schultz, Stefanie Friedrich, Emelie Berglund, Firas Tarish, Anna Tanoglidi, Yao Liu, Ludvig Bergenstråhle, Andrew Erickson, Thomas Helleday, Alastair D. Lamb, Erik Sonnhammer () and Joakim Lundeberg ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33069-3

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