Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and their expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.
bioRxiv : the preprint server for biology. 2024 Aug 23*** epublish ***
Michael J Schmidt, Amin Naghdloo, Rishvanth K Prabakar, Mohamed Kamal, Radu Cadaneanu, Isla P Garraway, Michael Lewis, Ana Aparicio, Amado Zurita-Saavedra, Paul Corn, Peter Kuhn, Kenneth J Pienta, Sarah R Amend, James Hicks
Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, California, USA., Department of Urology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and VA Greater Los Angeles, University of California, Los Angeles, Los Angeles, California, USA., VA Greater Los Angeles Medical Center, Los Angeles, CA, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.