Profilin 1 maintains cell cycle fidelity to prevent unscheduled genome doubling and polyploidy in cancer
Posted on: 10 August 2026
Preprint posted on 15 May 2026
One gene loss, two surveillance mechanisms broken: how cancer cells prevent genome doubling.
Selected by Akshata Samel
Categories: cancer biology, cell biology, molecular biology
Background:
Whole-genome doubling (WGD) is one of the most dramatic events in cancer evolution, where the entire chromosome set duplicates, creating a tetraploid intermediate that frequently evolves toward aneuploidy and chromosomal instability. It occurs in roughly 37% of primary tumors and over half of
metastatic solid tumors, and while it imposes some proliferative cost, it also gives cancer cells a powerful substrate for rapid adaptation and therapy resistance.
The longstanding puzzle has been this: cells have robust surveillance mechanisms to prevent WGD. The tumor suppressor p53 sits at the center of this surveillance, enforcing arrest in response to tetraploidy, centrosome amplification, and replication stress. And yet, a substantial fraction of WGD events arise in tumors that still carry wild-type p53. Something is allowing these cells to double their genome while flying under the radar.
Profilin 1 has classically been known as an actin-binding protein involved in cytoskeletal dynamics, but accumulating evidence points to a broader role in cell cycle regulation, particularly in DNA replication control and mitotic progression. Importantly, PFN1 loss-of-function mutations were previously identified in osteosarcomas, one of the cancer types with the highest prevalence of WGD, and in those tumors, PFN1 loss consistently preceded the genome doubling event. It suggests PFN1 inactivation is not just a passenger mutation but an early permissive event that opens the door to genome reduplication. This preprint sets out to understand exactly how.
Key findings of the preprint:
Mitotic bypass as a replication-based route to whole-genome doubling
While previous work from the same group had shown that PFN1 loss leads to cytokinesis failure and tetraploid cell formation, that alone could not account for the full extent of genome doubling observed. The central finding of this preprint is that mitotic bypass is the missing piece. Using FUCCI live-cell imaging, the authors showed that roughly one-third of PFN1- deficient cells simply exit G2 into a G1-like state without ever dividing, and then re-enter S phase and replicate their already
doubled genome. This establishes a clean replication-based route to polyploidy in cells that still carry functional p53, which is the key point.
A coordinated shutdown of the mitotic program
Digging into the mechanism, quantitative proteomics revealed a coordinated downregulation of mitotic regulators — CDK1, PLK1, CKS2 — in PFN1-deficient cells. This is not simply a population shifted toward G1. The authors carefully ruled that out. Instead, it reflects a specific biochemical signature of impaired mitotic commitment, where cells can initiate G2 but never fully cross the threshold into mitosis.
Checkpoint evasion, chemotherapy resistance, and metastasis
p53 was present in these cells but failed to scale up appropriately in response to tetraploidy or replication stress. The increased expression of nuclear MDM2 kept p53 suppressed even as the genome doubled and chromosomal instability accumulated. The consequence was tangible: PFN1-deficient cells were markedly more resistant to doxorubicin and nocodazole, and in an orthotopic osteosarcoma model, showed significantly higher metastatic burden in the lungs.
What I like about the preprint:
What makes this preprint particularly compelling is that it tackles a genuinely open question in cancer biology — how do cells double their genome with wild-type p53 present? That paradox has been noted in large-scale genomic analyses for years, but mechanistic explanations in p53- proficient cells have been hard to come by. This paper offers a concrete and well-supported answer.
The use of the FUCCI live-cell imaging system is particularly elegant here. By labeling cells in G1, S, and G2 with distinct fluorescent signals, the authors can watch individual cells in real time as they exit G2 without ever entering mitosis, transitioning directly into a G1-like state without any nuclear envelope breakdown or chromosome segregation. Seeing mitotic bypass play out cell by cell, across a 72-hour imaging window, makes the phenotype impossible to argue with in a way that endpoint assays simply cannot.
There is also something satisfying about the two-hit logic of the mechanism. PFN1 loss does not just create polyploid cells, but it simultaneously disables the checkpoint that would normally catch and eliminate them. That combination is what makes it such an efficient driver of genome instability, and it explains why PFN1 loss correlates so strongly with WGD across multiple cancer types in the TCGA data. Finally, the chemotherapy resistance data and the metastasis model follow naturally from the biology, and the pan-cancer association with WGD gives the findings immediate clinical relevance beyond osteosarcoma.
Future directions:
The most pressing next step would be to identify the direct mechanistic link between PFN1 loss and MDM2 nuclear accumulation. The authors rule out genomic amplification at the MDM2 locus, but the upstream connection remains undefined. Mapping that pathway would significantly strengthen the model and potentially reveal new therapeutic targets.
Understanding what drives cell fate heterogeneity within the PFN1-deficient population would be another valuable direction. Since not all cells undergo mitotic bypass, single-cell transcriptomics or proteomics on sorted populations, cells that bypassed mitosis versus those that divided normally, could reveal what tips the balance.
Finally, given the chemotherapy resistance profile of PFN1-deficient cells, exploring whether targeting the endoreplication machinery or other vulnerabilities specific to the polyploid state could be therapeutically exploited in PFN1-low tumors would be a natural and clinically relevant extension of this work.
Questions for authors:
- MDM2 nuclear accumulation appears to be the key mechanism suppressing p53 after tetraploidy — but what drives MDM2 upregulation upon PFN1 loss in the first place? Is there a direct mechanistic link between PFN1 and MDM2 regulation?
- Given that PFN1-deficient cells are resistant to nocodazole and doxorubicin but not to olaparib, could combination therapies targeting the endoreplication machinery alongside PARP inhibition be a viable therapeutic strategy in PFN1-low tumors?
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| List by | Carolina Tanigushi |
October in preprints – DevBio & Stem cell biology
Each month, preLighters with expertise across developmental and stem cell biology nominate a few recent developmental and stem cell biology (and related) preprints they’re excited about and explain in a single paragraph why. Short, snappy picks from working scientists — a quick way to spot fresh ideas, bold methods and papers worth reading in full. These preprints can all be found in the October preprint list published on the Node.
| List by | Deevitha Balasubramanian et al. |
October in preprints – Cell biology edition
Different preLighters, with expertise across cell biology, have worked together to create this preprint reading list for researchers with an interest in cell biology. This month, most picks fall under (1) Cell organelles and organisation, followed by (2) Mechanosignaling and mechanotransduction, (3) Cell cycle and division and (4) Cell migration
| List by | Matthew Davies et al. |
September in preprints – Cell biology edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading list. This month, categories include: (1) Cell organelles and organisation, (2) Cell signalling and mechanosensing, (3) Cell metabolism, (4) Cell cycle and division, (5) Cell migration
| List by | Sristilekha Nath et al. |
June in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: (1) Cell organelles and organisation (2) Cell signaling and mechanosensation (3) Genetics/gene expression (4) Biochemistry (5) Cytoskeleton
| List by | Barbora Knotkova et al. |
May in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) Biochemistry/metabolism 2) Cancer cell Biology 3) Cell adhesion, migration and cytoskeleton 4) Cell organelles and organisation 5) Cell signalling and 6) Genetics
| List by | Barbora Knotkova et al. |
Keystone Symposium – Metabolic and Nutritional Control of Development and Cell Fate
This preList contains preprints discussed during the Metabolic and Nutritional Control of Development and Cell Fate Keystone Symposia. This conference was organized by Lydia Finley and Ralph J. DeBerardinis and held in the Wylie Center and Tupper Manor at Endicott College, Beverly, MA, United States from May 7th to 9th 2025. This meeting marked the first in-person gathering of leading researchers exploring how metabolism influences development, including processes like cell fate, tissue patterning, and organ function, through nutrient availability and metabolic regulation. By integrating modern metabolic tools with genetic and epidemiological insights across model organisms, this event highlighted key mechanisms and identified open questions to advance the emerging field of developmental metabolism.
| List by | Virginia Savy, Martin Estermann |
April in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell cycle and division 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) (epi)genetics
| List by | Vibha SINGH et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
February in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry and cell metabolism 2) cell organelles and organisation 3) cell signalling, migration and mechanosensing
| List by | Barbora Knotkova et al. |
Community-driven preList – Immunology
In this community-driven preList, a group of preLighters, with expertise in different areas of immunology have worked together to create this preprint reading list.
| List by | Felipe Del Valle Batalla et al. |
January in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Barbora Knotkova et al. |
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |