Pierre Foidart, Medical Oncologist, Head of Clinic at CHU de Liège, shared a post on LinkedIn:
“Whole Genome Doubling is not merely a byproduct of tumor evolution but actively contributes to progression of breast cancer!
Absolutely thrilled to share that our work has just been published online in Cancer Cell.
In this study, we investigated how whole genome doubling (WGD) shapes tumor evolution. Using complementary approaches – including two experimental models of WGD acquisition, patient-derived organoids, public datasets, and matched diploid/tetraploid metastases – we show that WGD is not just a genomic event, but a key driver of tumor–immune interactions.
Key findings:
- WGD increases transcriptomic and epigenetic heterogeneity.
- WGD+ tumors grow faster in immunocompetent settings by escaping CD8+ T cell control.
- Although initially more immunogenic, WGD+ cells evade immune recognition through impaired interferon responsiveness and reduced antigen presentation.
- Mechanistically, reduced KDM6 activity leads to increased H3K27me3 and repression of interferon signaling, linked to metabolic changes (αKG/succinate ratio).
- Targeting PRC2 (EED inhibition) preferentially suppresses WGD+ tumors and restores immune visibility.
These results identify WGD as a key driver of immune evasion in breast cancer and suggest combined PRC2 and PD-1 blockade as a potential therapeutic strategy.
This work is the result of a truly collaborative effort, and I’m deeply grateful to everyone who contributed their expertise, time, and energy along the way. I am especially thankful to Kornelia Polyak for her exceptional mentorship and trust throughout my postdoc, and to all members of the Polyak Lab, especially Xinran Cai, Zheqi (Vaciry) Li and Marco Seehawer. It was a privilege to work at the Dana-Farber Cancer Institute and be part of such a stimulating and supportive environment.
I also sincerely thank Agnès Noël, Guy Jerusalem, Nor Eddine Sounni and the Institut de Cancérologie Arsène Burny at CHU de Liège (Frédéric Kridelka) for their continued support.
Finally, I am grateful to the funding bodies that made my postdoc possible: Wallonie-Bruxelles International (WBI), Télévie, F.R.S. – FNRS, Belgian American Educational Foundation (Emile Boulpaep), and Fondation Léon Fredericq.
Excited to see where this leads next, in collaboration with Pierre Close and the Fondation contre le Cancer – Stichting tegen Kanker.”
Title: Whole-genome doubling drives immune evasion by silencing antigen presentation
Authors: Pierre Foidart, Zheqi Li, Xinran Cai, Marco Seehawer, Daniel Brown, Amatullah Tawawalla, Pilar Baldominos, Salma Parvin, Jun Nishida, Ernesto Rojas-Jimenez, Triet Bui, Benedetto Diciaccio, Rahul Kumar, Brent Schlegel, Marie-Anne Goyette, TashJae Scales, Pengze Yan, Xintao Qiu, Rong Li, Yijia Jiang, Yingtian Xie, Mahmoud Aarabi, Xiao-Yun Huang, Laura Stevens, Paloma Cejas, Lise Mangiante, Cristina Irene Sotomayor Vivas, Kathleen Houlahan, Christina Curtis, Steffi Oesterreich, Isaac Harris, Anthony Letai, Adrian Lee, Henry Long, Judith Agudo, Kornelia Polyak
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