Polyploid cancer cells reveal signatures of chemotherapy resistance

doi:10.1038/s41388-024-03212-z

. 2024 Nov 22.

doi: 10.1038/s41388-024-03212-z. Online ahead of print.

Polyploid cancer cells reveal signatures of chemotherapy resistance

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. samend2@jhmi.edu.
¹² Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA. jameshic@usc.edu.

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

Polyploid cancer cells reveal signatures of chemotherapy resistance

Michael J Schmidt et al. Oncogene. 2024.

. 2024 Nov 22.

doi: 10.1038/s41388-024-03212-z. Online ahead of print.

Authors

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. samend2@jhmi.edu.
¹² Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA. jameshic@usc.edu.

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: The HDSCA technology described here is licensed to Epic Sciences. PK has ownership in Epic Sciences. JH discloses he is a member of the Clinical Advisory Board of Epic Sciences. KJP is a consultant for CUE Biopharma, Inc., and holds equity interest in CUE Biopharma, Inc., Keystone Biopharma, Inc., PEEL Therapeutics, Inc and Kreftect, Inc. SRA holds equity interest in Keystone Biopharma, Inc. Ethics Approval and Consent to Participate: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the University of Southern California Keck School of Medicine, MD Anderson (NCT01505868), and the VA of Los Angeles (PCC 2015-090980). Informed consent was obtained from all subjects involved in the study. Consent for Publication: All the authors agree to publish this paper.

Update of

Polyploid cancer cells reveal signatures of chemotherapy resistance.
Schmidt MJ, Naghdloo A, Prabakar RK, Kamal M, Cadaneanu R, Garraway IP, Lewis M, Aparicio A, Zurita-Saavedra A, Corn P, Kuhn P, Pienta KJ, Amend SR, Hicks J. Schmidt MJ, et al. bioRxiv [Preprint]. 2024 Aug 23:2024.08.19.608632. doi: 10.1101/2024.08.19.608632. bioRxiv. 2024. Update in: Oncogene. 2024 Nov 22. doi: 10.1038/s41388-024-03212-z PMID: 39229204 Free PMC article. Updated. Preprint.
Polyploid cancer cells reveal signatures of chemotherapy resistance.
Hicks J, Schmidt M, Nahgdloo A, Prabakar R, Kamal M, Cadaneanu R, Garraway I, Lewis M, Aparicio A, Zurita A, Corn P, Kuhn P, Pienta K, Amend S. Hicks J, et al. Res Sq [Preprint]. 2024 Oct 14:rs.3.rs-4921634. doi: 10.21203/rs.3.rs-4921634/v1. Res Sq. 2024. Update in: Oncogene. 2024 Nov 22. doi: 10.1038/s41388-024-03212-z PMID: 39483900 Free PMC article. Updated. Preprint.

References

1. Kurbegovic S, Berg KD, Thomsen FB, Gruschy L, Iversen P, Brasso K, et al. The risk of biochemical recurrence for intermediate-risk prostate cancer after radical prostatectomy. Scand J Urol. 2017;51:450–6. - PubMed - DOI
1. Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N. Engl J Med. 2016;375:209–19. - PubMed - PMC - DOI
1. Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thurlimann B, et al. Annual hazard rates of recurrence for breast cancer during 24 years of followup: Results from the international breast cancer study group trials i to v. J Clin Oncol. 2016;34:927–35. - PubMed - PMC - DOI
1. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21:3233. - PubMed - PMC - DOI
1. Ashdown ML, Robinson AP, Yatomi-Clarke SL, Ashdown ML, Allison A, Abbott D, et al. Chemotherapy for late-stage cancer patients: Meta-analysis of complete response rates. F1000Res. 2015;4:232. - PubMed - PMC - DOI

Grants and funding

W81XWH-20-10353, W81XWH-22-1-0680/U.S. Department of Defense (United States Department of Defense)

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

[1] Kurbegovic S, Berg KD, Thomsen FB, Gruschy L, Iversen P, Brasso K, et al. The risk of biochemical recurrence for intermediate-risk prostate cancer after radical prostatectomy. Scand J Urol. 2017;51:450–6. - PubMed - DOI

[2] Kurbegovic S, Berg KD, Thomsen FB, Gruschy L, Iversen P, Brasso K, et al. The risk of biochemical recurrence for intermediate-risk prostate cancer after radical prostatectomy. Scand J Urol. 2017;51:450–6. - PubMed - DOI

[3] Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N. Engl J Med. 2016;375:209–19. - PubMed - PMC - DOI

[4] Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N. Engl J Med. 2016;375:209–19. - PubMed - PMC - DOI

[5] Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thurlimann B, et al. Annual hazard rates of recurrence for breast cancer during 24 years of followup: Results from the international breast cancer study group trials i to v. J Clin Oncol. 2016;34:927–35. - PubMed - PMC - DOI

[6] Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thurlimann B, et al. Annual hazard rates of recurrence for breast cancer during 24 years of followup: Results from the international breast cancer study group trials i to v. J Clin Oncol. 2016;34:927–35. - PubMed - PMC - DOI

[7] Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21:3233. - PubMed - PMC - DOI

[8] Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21:3233. - PubMed - PMC - DOI

[9] Ashdown ML, Robinson AP, Yatomi-Clarke SL, Ashdown ML, Allison A, Abbott D, et al. Chemotherapy for late-stage cancer patients: Meta-analysis of complete response rates. F1000Res. 2015;4:232. - PubMed - PMC - DOI

[10] Ashdown ML, Robinson AP, Yatomi-Clarke SL, Ashdown ML, Allison A, Abbott D, et al. Chemotherapy for late-stage cancer patients: Meta-analysis of complete response rates. F1000Res. 2015;4:232. - PubMed - PMC - DOI

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Polyploid cancer cells reveal signatures of chemotherapy resistance

Affiliations

Polyploid cancer cells reveal signatures of chemotherapy resistance

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

Similar articles

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous

Abstract

Conflict of interest statement

Update of

Similar articles

References

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous