Understanding Metastasis: Unveiling the First Steps of Melanoma Spread

One of the major questions in cancer research still concerns the process by which tumor cells can establish themselves in other organs, leading to a generalized disease that is difficult to cure. A widely discussed concept suggests that this is a form of faulty organ development, such as an attempt by breast gland cells to form a breast gland in the liver or lungs. Since organ development is naturally complete in adults, it is largely unknown how such faulty attempts at organ formation occur.

These questions are often analyzed in animal models, where various technical possibilities exist to uncover mechanisms. However, direct analysis in patients has not yet been systematically attempted. Several research teams from the University Hospital and University of Regensburg, the Leibniz Institute for Immunotherapy (LIT), Fraunhofer ITEM, the University Hospital and University of Tübingen, as well as others from the metastasis research network (SFB/TRR 305), have now joined forces under the leadership of Assoc. Prof. Melanie Werner-Klein (Head of LIT Cooperation Group “Translational Immunobiology of Early Systemic Cancer” and group leader at the Chair of Experimental Medicine and Therapy Research at the University of Regensburg) and Prof. Christoph Klein (Director of Chair of Experimental Medicine and Therapy Research) to shed light on this issue.

They examined the lymph nodes of approximately 500 patients with malignant melanoma, a type of skin cancer, for early metastases. Various marker proteins were used to make cells visible through staining. The researchers identified a protein (MCSP) whose presence on disseminated melanoma cells was associated with a significantly worse prognosis. Patients with MCSP-positive melanoma cells had drastically poorer prospects across all three survival categories (disease-free, melanoma-specific, and overall survival), even in cases where only one such cell per two million lymph node cells was detected. The researchers were then able to read the activated genes from about 150 of these very rare MCSP-positive cells to obtain initial insights into their cell functions.

The findings were astonishing. From the very first steps upon arriving in the foreign organ (the lymph node) to the development of micro- and macroscopic metastases, cancer cells change their phenotype multiple times. In line with the concept of faulty organ formation, the embryonic gene program of UV-protective cells, the melanocytes, is activated. During embryonic development, melanocyte precursor cells migrate from the neural crest to the skin. This very neural crest stem cell program is activated during metastasis formation, as a response to immune attacks by T cells on cancer cells that survive the assaults. The colony can then form because the neural crest program is also associated with immunosuppression. Once larger colonies have formed, the immune response weakens—the T cells become exhausted, and the cancer can progress.

These insights into the process of metastasis formation highlight potential therapeutic targets that could help nip the development of metastases in the bud. For instance, the identified MCSP could become a therapeutic target, or enhancing early immune defense might prevent melanoma cells from evading immune attacks through the neural crest stem cell program.

For more information, please visit the full article in the journal Nature Cancer:

Guetter S, König C, Koerkel-Qu H, Markiewicz A, Scheitler S, Katzer M, Berneburg M, Renner P, Cucuruz B, Guttenberger L, Naimer V, Weidele K, Treitschke S, Werno C, Jaser H, Bargmann T, Braun A, Weber F, Evert K, Rochwarger A, Schürch CM, Limm K, Oefner PJ, Rachel R, Baumann F, Warfsmann J, Schmidleithner L, Guetter K, Mohammadi P, Ulmer A, Haferkamp S, Klein C.A., Werner-Klein M MCSP+ metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization. Nature Cancer. 2025 May 16. doi:10.1038/s43018-025-00963-w. PMID: 40379833

https://www.nature.com/articles/s43018-025-00963-w

See also the News & Views article in Nature Cancer:

Karras, P., Marine, JC. Fishing for melanoma metastasis-initiating cells in lymph nodes. Nat Cancer (2025). https://doi.org/10.1038/s43018-025-00973-8

https://www.nature.com/articles/s43018-025-00973-8