The Challenge of Therapeutic Resistance

Prostate and breast cancers, among the most common malignancies, often respond well to initial treatments. However, recurrence rates are alarmingly high [1-3]. Late-stage metastatic cancers pose an even greater challenge, with chemotherapy offering limited success [4-5]. Despite extensive research into the mechanisms of therapy resistance, it remains the cause of over 90% of cancer-related deaths and urgently needs to be addressed [6-8].

The Role of Polyploid Cancer Cells

Our study focuses on large polyploid cancer cells, which have been associated with late disease stages, poor prognosis, and therapy resistance across various cancer types [9-13]. These cells can arise in response to stressors, including chemotherapy agents like docetaxel and cisplatin [14-17]. Whole genome doubling (WGD) events that lead to polyploidy are poor prognostic indicators and may provide cancer cells with the ability to evolve and survive therapy [18-21].

Our Study: Key Findings

In our research, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients. We discovered that the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival (Figure 1).

In vitro, we examined induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin. Through single-cell DNA sequencing, RNA sequencing, and protein immunofluorescence, we identified novel RNA and protein markers linked to chemotherapy resistance, including HOMER1, TNFRSF9, and LRP1. These markers were present in a subset of patient CTCs and are associated with recurrence in public gene expression data. We were also able to obtain a progeny clone descended from one polyploid cancer cell that retained surviving polyploid cancer cell markers.

Implications for Cancer Treatment

Our findings highlight the prognostic significance of large polyploid tumor cells and their role in chemotherapy resistance. The expression of markers tied to cancer relapse offers new potential avenues for therapeutic development. By targeting these markers, we may improve treatment outcomes and reduce recurrence rates.

Future Directions

While our study provides valuable insights, it also raises important questions. The presence of polyploid cancer cells in late-stage disease suggests a need for further research into their role in early-stage cancers. Additionally, understanding how these cells interact with their environment and other cancer cells could provide new therapeutic targets.

Future studies should explore the roles of identified markers like TNFRSF9, HOMER1, and LRP1 in chemotherapy resistance. Investigating these markers in vivo, using mouse models or patient-derived xenografts, will be crucial in translating our findings into clinical applications.

Conclusion

Our research underscores the importance of understanding the role of polyploid cancer cells in therapy resistance and disease recurrence. By identifying novel biomarkers and potential therapeutic targets, we hope to pave the way for more effective cancer treatments. Theoretically, it only takes one polyploid cancer cell to initiate relapse. As we continue to unravel the complexities of cancer biology, understanding and combating the mechanisms of resistance these cells utilize will aid in deconvoluting therapy resistance.

References

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