Utikal, J. | bioRxiv Science

bioRxiv2025

Multiomic profiling of a unique in-transit melanoma cohort identifies melanoma differentiation as predictor of tumor progression and therapy response

Melanoma patients with in-transit metastasis (ITM), a stage of disease where melanoma has metastasized to sites in between the primary lesion and draining lymph node, vary significantly in their clinical outcomes, but the biology driving differential outcomes in ITM is poorly understood. To elucidate the mechanisms of differential outcomes, we utilized multimodal molecular profiling (WES, RNA-seq, highly multiplexed immunofluorescence, spatial transcriptomics) in 1) evolutionary analysis of longitudinal tumor samples and 2) identifying prognostic tumor intrinsic and microenvironmental features in a unique cohort of patients with unresectable ITM. Among other findings, we observed a persistent dedifferentiated AXL/NGFR clonal lineage pre-existing and following immune checkpoint blockade in in-transit and distant metastases. Concordantly, we found that low pigmentation and high T cell exhaustion signatures were independently associated with distant progression. Our findings highlight tumor cell state and immune dysfunction as key predictors and potential biomarkers of metastatic risk in ITM. STATEMENT OF SIGNIFICANCEWhat drives distant progression in melanoma is unclear. Analyzing tumor and immune features in a rare in-transit melanoma patient cohort, we identify biological signals highlighting how immune and tumor states observable in pre-distant metastasis melanomas shape long-term outcomes, and nominate potential prognostic biomarkers.

cancer biology↗

bioRxiv2025

Corticotropin-releasing hormone in melanoma and non-melanoma skin cancer.

BackgroundCorticotropin-releasing hormone (CRH) is involved in the regulation of immunological and cellular processes. Recently, CRH has been found to be expressed in skin cancers, where its expression appears to correlate with the degree of malignancy. ObjectiveThis study correlates CRH expression in melanoma metastases with patient survival and compares the intensity of CRH expression in melanoma to that in less aggressive skin cancer entities. MethodsTissue microarrays with cores from 94 melanomas and 40 melanocytic nevi and 51 slides from 41 basal cell carcinomas (BCC) and 10 squamous cell carcinomas (SCC) were immunohistochemically stained for CRH. The intensity of CRH expression in melanoma metastases was stratified by sex and correlated with patient survival. Furthermore, proliferation and apoptosis were assessed in CRH-stimulated A431 cells using enzyme-linked immunosorbent assays and an apoptosis detection kit. ResultsThe intensity of CRH expression was higher in primary melanomas than in melanocytic nevi. Higher CRH expression was also found in melanoma metastases from women compared to men. However, higher CRH expression was correlated with reduced overall survival only in men. Compared to melanoma, BCCs and SCCs showed weaker CRH expression, which was in line with the finding that in vitro, CRH stimulation of the A431 cells reduced their proliferative activity. ConclusionCRH does not necessarily correlate with the degree of malignancy, as semi-malignant cancers such as BCC show higher levels of CRH expression than SCCs. In melanoma, CRH expression in metastases may be an important prognostic factor for overall survival in men, which needs further evaluation. Statement of contributionMarcel Mueller and Susanne Melchers performed all experiments and wrote the first draft of the manuscript. Iris Mueller helped with the experiments and reviewed the manuscript, Jochen Utikal assembled the tissue microarrays and reviewed the manuscript, Julia Krug helped with the figures and reviewed the manuscript, and Astrid Schmieder designed and supervised the project and corrected the manuscript.

cancer biology↗