Polyploid cancer cells reveal signatures of chemotherapy resistance

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

doi:10.1038/s41388-024-03212-z

Polyploid cancer cells reveal signatures of chemotherapy resistance

Oncogene. 2024 Nov 22. doi: 10.1038/s41388-024-03212-z. Online ahead of print.

Authors

Michael J Schmidt^{1

2}, Amin Naghdloo¹, Rishvanth K Prabakar^{1

3}, Mohamed Kamal^{1

4}, Radu Cadaneanu⁵, Isla P Garraway⁵, Michael Lewis^{6

7

8}, Ana Aparicio⁹, Amado Zurita-Saavedra⁹, Paul Corn⁹, Peter Kuhn¹, Kenneth J Pienta¹⁰, Sarah R Amend¹¹, James Hicks¹²

Affiliations

¹ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA.
² Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
⁴ Department of Zoology, Faculty of Science, Benha University, Benha, Egypt.
⁵ 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, CA, USA.
⁶ VA Greater Los Angeles Medical Center, Los Angeles, CA, USA.
⁷ Departments of Medicine and Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Center for Cancer Research and Cellular Therapeutics, Clark, Atlanta, GA, USA.
⁹ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹² Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA. [email protected].

PMID: 39578659
DOI: 10.1038/s41388-024-03212-z

Abstract

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 are 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 the expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.

Abstract

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