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Tumoral CD24 tunes platelet binding and pro-metastatic functions

Vincent Mittelheisser, Cristina Liboni, Clarisse Mouriaux, Silvia Maria Grazia Trivigno, Louis Bochler, Maria J. Garcia-Leon, Annabel Larnicol, Laetitia Paulen, Tristan Stemmelen, Pierre Mangin, Olivier Lefebvre, Jacky G. Goetz

Posted on: 16 June 2025 , updated on: 18 June 2025

Preprint posted on 15 April 2025

Metastatic Matchmaking: CD24 Brings Tumor Cells and Platelets Together

Selected by Harvey Roweth

Categories: cancer biology

📖 Background 📖

Platelets, while best known for their roles in blood clotting, are increasingly appreciated as active players in cancer progression. In particular, platelets can bind to circulating tumour cells inside of blood vessels, which protects them from the immune system and enables their metastasis to distant organs. Despite evidence suggesting that platelet-associated tumour cells are more likely to complete their metastatic journey,1 the specific ligands and receptors connecting these two cells remain only partially understood. Uncovering how platelets bind to tumour cells and finding ways to prevent these attachments happening in circulation would therefore offer a novel approach to limit metastasis.

In their preprint, Mittelheisser and team identify CD24 on tumour cells as a key regulator for platelet binding and demonstrate its role in promoting lung metastasis in mouse models.

💡 Key Findings 💡

  • CD24 allows tumour cells to ensnare activated platelets:
    Taking inspiration from their previous work exploring platelets and metastatic outgrowth,2 the authors tested the platelet-binding properties of several mouse cancer cell lines and showed that the CD24high and highly metastatic triple negative breast cancer cell line 4T1 was able to bind more platelets than CD24low cells. Silencing CD24 expression with short hairpin RNA reversed the platelet binding properties of 4T1 cells, highlighting the importance of this specific receptor.
  • Loss of CD24 impairs metastasis in mice:
    In mouse models of blood-borne metastasis, the authors demonstrated—using in vivo imaging over several time points—that lowering CD24 expression in breast cancer cells reduces their ability to colonise the lung.

Figure 1. The authors discover that platelets were much better at binding to tumour cells expressing high levels of CD24, a membrane-tethered glycoprotein receptor that can connect to cells via P-selectin (CD62p). Activated platelets express high levels of CD62p on their surface, suggesting that this is how they can preferentially bind to CD24-expressing tumour cells. Created using biorender.com.

🤔 Why I found this preprint interesting 🤔

I’ve studied platelet biology for over a decade, and I’m particularly interested in how platelets promote cancer progression. While animal models highlight the importance of platelets in metastasis, there is plenty more to learn about the underlying mechanisms and whether these can be targeted to improve the lives of cancer patients. In their preprint, the authors start by screening several cancer cells lines, comparing their known metastatic potential with their ability to bind platelets in vitro and their expression of platelet-binding receptors. I liked this unorthodox, yet refreshing approach, which led to their selection of CD24, which has been studied extensively as a cancer stem cell marker but not explored in the context of platelet biology. The authors show that CD24 can bind CD62p, which is highly expressed on the surface of activated platelets. Therefore, tumour cells expressing CD24 may hold a selective advantage when it comes to binding and retaining activated platelets to increase their chances of successful metastasis.

🎯 Takeaway message 🎯

Mittelheisser and colleagues provide compelling evidence that CD24 enhances tumour-platelet crosstalk, driving both the early intravascular seeding and prolonged outgrowth of tumour cells in the lung environment. This work expands our understanding of how cancer cells exploit platelets to their advantage and highlights CD24 as a possible therapeutic target in limiting platelet-tumour cell interactions and maybe even metastasis.

References

  1. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20:576-590. doi: 10.1016/j.ccr.2011.09.009
  2. Garcia-Leon MJ, Liboni C, Mittelheisser V, Bochler L, Follain G, Mouriaux C, Busnelli I, Larnicol A, Colin F, Peralta M, et al. Platelets favor the outgrowth of established metastases. Nat Commun. 2024;15:3297. doi: 10.1038/s41467-024-47516-w

 

doi: https://doi.org/10.1242/prelights.40868

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Author's response

Vincent Mittelheisser, Cristina Liboni, and Jacky G. Goetz shared

Future directions and questions for the authors

 

  1. I found it interesting that platelet-driven tumour cell clustering is supported by CD24. In the clustering experiments where tumour cells were supplemented with either plasma or platelet-rich plasma (PRP), did you also consider a plasma-free control? I ask because plasma also contains soluble P-selectin which would theoretically bind to 4T1 cells and might influence cluster formation.

 

For this project, we aimed at closely mimicking the physio-pathological conditions. Since tumour cells are unlikely to encounter a plasma-free environment in vivo, we used plasma depleted in platelets as a control to confirm that the observed clustering was mostly induced by platelets and not by soluble P-selectin. Yet, one cannot fully rule out that free soluble P-Selectin could contribute to some extent to this response.

 

  1. Do you anticipate any platelet-independent effects of CD24 beyond endothelial cells that could also contribute to reduced lung colonization of shCD24 4T1 cells?

 

One of the major ligands of CD24 is P-selectin. Previous studies have highlighted P-selectin’s role in tumour metastasis, particularly in favouring the arrest of tumour cells in the lungs1. However, whether the P-selectin involved originates from platelets or endothelial cells has remained ill-described. In our study, by inducing short-term thrombocytopenia pharmacologically at the time of tumour cell injection, we demonstrated that platelet-derived P-selectin mediates early lung seeding of tumour cells. Nonetheless, we cannot rule out later platelet-independent roles of CD24 in controlling metastatic outgrowth and this is actually what we have been testing in our study. Another key ligand of CD24 is Siglec-10, expressed by macrophages. The interaction between tumour cell-borne CD24 and macrophage Siglec-10 serves as a “don’t eat me” signal, protecting tumour cells from phagocytosis2. Thus, CD24 knockdown in tumour cells could promote their phagocytic clearance. Yet, we did not observe increased macrophage infiltration in the lungs bearing control versus CD24 knockdown metastases, suggesting this not to be a major mechanism involved in our model. Additionally, the potency of the CD24 “don’t eat me” signal has recently been questioned in a preprint from the Weiskopf lab3. Taken together, CD24 exerts platelet-independent effects on the immune system later during the metastatic progression. Indeed, as observed in our model knocking down CD24 expression at the tumour cells surface promotes a lymphoid response characterized by an enhanced infiltration of NK-, B- and T cells within the lung parenchyma. Nevertheless, we could not observe any changes in monocytes or macrophages populations that could suggest an increased phagocytic activity. The CD24-mediated platelet-independent effects on the immune system yet needs further in-depth investigation.

 

  1. Do you have plans to test the role of CD24 in legitimate metastasis beyond lung colonization (e.g. inject shCD42 4T1 cells into a mammary fat pad and measure lung metastasis)? Or would you expect shCD24 cells to have compromised primary tumour growth that would in itself limit metastasis?

 

Although we did not observe any proliferation defects in vitro or in vivo in experimental metastasis models suggesting that shCD24 cells would not have impaired primary tumour growth, we do not plan to assess the role of CD24 in spontaneous metastasis using mammary fat pad injections. This is because low CD24 expression is known to be associated with reduced metastasis in both murine models and humans4,5 and because we aimed at focusing our approach on vascular steps of metastasis. Nevertheless, studying spontaneous metastasis from a primary tumour remains highly relevant when investigating platelet involvement in cancer progression.

 

  1. While you hypothesise that the CD24-mediated tumour-cell-platelet interaction controls the long-term composition of the tumour immune microenvironment. Could this also be because there is less tumour burden in the lungs of mice injected with shCD24 cells and therefore less of an inflammatory response?

 

We showed that CD24 knockdown impairs tumour cell lung seeding. To determine if the lower metastatic burden reduces the inflammatory response, we examined the correlation between the number of metastatic foci and CD45+ cell infiltration. We found no correlation, suggesting that metastatic burden does not affect the level of inflammation. Yet, further exploration would allow us to firmly rule this out.

References:

  1. Kim, Y. J., Borsig, L., Varki, N. M. & Varki, A. P-selectin deficiency attenuates tumor growth and metastasis. Proceedings of the National Academy of Sciences 95, 9325–9330 (1998).
  2. Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).
  3. Allen, J. et al. CD47 predominates over CD24 as a macrophage immune checkpoint in cancer. 2024.11.25.625185 Preprint at https://doi.org/10.1101/2024.11.25.625185 (2024).
  4. Hong, P. et al. CD24 promotes metastasis and chemoresistance by directly targeting Arf6-ERK pathway in esophageal squamous cell carcinoma. Cancer Lett 594, 216994 (2024).
  5. Park, G. et al. High Level CD24 Expression Is Correlated to Higher Metastatic Potential of Breast Cancer Cells. Blood 104, 2859 (2004).

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