C-T.25: Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer
Authors
Lachlan Cain
Peter MacCallum Cancer Centre
James Comben
Peter MacCallum Cancer Centre
Yangyi Zhang
St. Vincent's Institute of Medical Research
Timothy Semple
Peter MacCallum Cancer Centre
Sara Alaei
Peter MacCallum Cancer Centre
David Yoannidis
Peter MacCallum Cancer Centre
Luciano Martelotto
BD Biosciences
Catherine Mitchell
Peter MacCallum Cancer Centre
Anupama Pasam
Peter MacCallum Cancer Centre
Richard Young
Peter MacCallum Cancer Centre
Benjamin Blyth
Peter MacCallum Cancer Centre
Joy Hendley
Peter MacCallum Cancer Centre
Yuzhou Feng
Heather Thorne
Peter MacCallum Cancer Centre
Roslyn Wallace
Peter MacCallum Cancer Centre
Joanna Chan
Peter MacCallum Cancer Centre
Julia Como
The University of Melbourne
Lisa Devereux
Peter MacCallum Cancer Centre
Scott Williams
Peter MacCallum Cancer Centre
Belinda Parker
Peter MacCallum Cancer Centre
Paul Neeson
Peter MacCallum Cancer Centre
David Goode
Peter MacCallum Cancer Centre
Richard Pearson
Peter MacCallum Cancer Centre
Luc Furic
Peter MacCallum Cancer Centre
Shahneen Sandhu
Peter MacCallum Cancer Centre
Anna Trigos
Peter MacCallum Cancer Centre
Keywords
Cancer Evolution, Tumour Heterogeneity, Tumour Genomics, Single-cell RNAseq, Multi-omic Integration, Prostate Cancer, Archetype Analysis
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The evolution from low grade to metastatic tumour is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the external microenvironmental factors. To define mechanisms underpinning metastatic development, we focused on metastatic castration-resistant prostate cancer (mCRPC) and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions from 9 patients by rapid autopsy. We found that intra-tumour heterogeneity is an indicator of key evolutionary processes, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. Unexpectedly, microenvironments only played a limited role while clonal evolution primarily promoted transcriptional noise. Intra-patient functional convergence of tumour ecosystems was observed across metastases, showing system-level selection pressures that drive the heterogeneity landscape of mCRPC. Our findings reveal functional evolutionary convergence of metastatic disease into units of intra-tumour heterogeneity, identifying critical determinants for therapeutic targeting.
Co-authors: Sirui Weng, Lachlan Cain, James Comben, Yangyi Zhang, Timothy Semple, Sara Alaei, David Yoannidis, Luciano Martelotto, Catherine Mitchell, Anupama Pasam, Richard J. Young, Benjamin Blyth, Joy Hendley, Yuzhou Feng, Heather Thorne, Roslyn Wallace, Joanna Chan, Julia Como, Lisa Devereux, Scott Williams, Belinda Parker, Paul Neeson, David L. Goode, Richard B. Pearson, Luc Furic, #Shahneen Sandhu, #Anna S. Trigos
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