Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer
Abstract
Abstract The evolution to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic heterogeneity in late-stage disease, we focus on metastatic castration-resistant prostate cancer and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions obtained from 9 patients through rapid autopsy. We find evolutionary convergence of intra-tumour heterogeneity, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. We find little evidence of the microenvironment driving transcriptional heterogeneity, but there are signatures of co-adaptation between the microenvironment and tumour cells. In contrast, clonal evolution primarily foster widespread transcriptional changes that did not result in de novo functional states. Intra-patient functional convergence of tumour ecosystems across metastases indicates system-level selection pressures that drive the heterogeneity landscape of metastatic castration-resistant prostate cancer. Our findings reveal functional evolutionary convergence of metastatic disease into distinct intra-tumour subpopulations, identifying critical determinants for therapeutic targeting.
Article Details
Authors (32)
Sirui Weng
Lachlan Cain
James Comben
Yangyi Zhang
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University
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
Himisha Beltran
Daniel Wetterskog
Scott Williams
Anthony T. Papenfuss
Belinda Parker
Paul Neeson
Gerhardt Attard
David Quigley
Department of Physics, University of Warwick 2 , Gibbet Hill Road, Coventry CV4 7AL,
David L. Goode
Richard B. Pearson
Luc Furic
Anna S. Trigos
Shahneen Sandhu
From the Sandra and Edward Meyer Cancer Center (J.D.W.) and the Department of Medicine (J.D.W., M.A.P.), Weill Cornell Medicine, and Memorial Sloan Kettering Cancer Center (M.A.P.) — both in New York; Istituto Oncologico Veneto, IRCCS, Padua (V.C.-S.), European Institute of Oncology, IRCCS, Milan (P.Q.), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola (M.G.), University of Siena and the Center for Immuno-Oncology, University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.) — all in Italy; Maria Sklodowska-Curie National Institute of Oncology, Warsaw, Poland (P.R.); Texas Oncology–Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.); University Hospital Essen, the German Cancer Consortium, the National Center for Tumor Diseases–West, the Research Alliance Ruhr, Research Center One Health, and University Duisburg-Essen — all in Essen, Germany (D.S.); the College of Medicine, Swansea University, Swansea (J.W.), Brist...