Vallius Tuulia, Shi Yingxiao, Novikov Edward, Pant Shishir M, Pelletier Roxanne, Chen Yu-An, Tefft Juliann B, Johnson Ajit Nirmal, Maliga Zoltan, Wan Guihong, Murphy George, Santagata Sandro, Semenov Yevgeniy R, Liu David, Lian Christine G, Sorger Peter K
Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.
Ludwig Center at Harvard.
bioRxiv. 2025 Jun 24:2025.06.21.660851. doi: 10.1101/2025.06.21.660851.
Early detection of melanoma through skin surveillance is critical for preventing metastatic progression. Primary cutaneous melanomas at early stage offer a unique opportunity to uncover fundamental mechanisms of tumor initiation, progression, and immune surveillance, but detailed spatial profiling of early disease remains limited. Here we integrate high-plex cyclic immunofluorescence (CyCIF) imaging, spatial transcriptomics, and conventional histology to identify factors associated with de-differentiation and dermal invasion in early-stage melanomas. We demonstrate a high level of variability from one primary cancer to the next, from one 100-300 cell microregion to the next within a single cancer, and from one cell to the next within a microregion. Intra-tumoral heterogeneity is influenced by local features of the microenvironment including proximity to T and myeloid cells and to perivascular environments. Thus, tumor plasticity and spatial heterogeneity arise early in melanoma development, potentially allowing for competition among multiple tumor states during the emergence of invasive disease.
通过皮肤监测早期发现黑色素瘤对于预防转移进展至关重要。早期原发性皮肤黑色素瘤为揭示肿瘤起始、进展和免疫监测的基本机制提供了独特的机会，但早期疾病的详细空间分析仍然有限。在这里，我们整合了高多重循环免疫荧光（CyCIF）成像、空间转录组学和传统组织学，以确定与早期黑色素瘤去分化和真皮侵袭相关的因素。我们证明了从一个原发性癌症到下一个原发性癌症、从单个癌症内的一个100 - 300细胞微区域到下一个微区域以及从一个微区域内的一个细胞到下一个细胞都存在高度变异性。肿瘤内异质性受微环境的局部特征影响，包括与T细胞、髓样细胞以及血管周围环境的接近程度。因此，肿瘤可塑性和空间异质性在黑色素瘤发展早期就出现了，这可能在侵袭性疾病出现期间允许多种肿瘤状态之间的竞争。
