Integrated Molecular and Spatial Analysis Reveals Evolutionary Dynamics and Tumor-Immune Interactions in In Situ and Invasive Acral Melanoma

Academic Background of the Paper

Melanoma is a type of skin cancer, and acral melanoma (AM) is a kind that occurs on non-exposed areas such as the palms, soles, and under the nails and is particularly common among Asian populations. However, this type of melanoma is often diagnosed at a late stage, leading to a poor prognosis. Early detection and prevention of AM can significantly improve patient outcomes. Although much research has been conducted in recent years on the genomic characteristics of advanced invasive acral melanoma (IAM), understanding of early-stage acral melanoma in situ (AMIS) remains very limited. Therefore, exploring the evolutionary dynamics of AM from the in situ stage to the invasive stage and its interactions with the tumor microenvironment (TME) is a crucial objective of this study.

Source of the Paper

This paper, authored by researchers Hengkang Liu, Qingwen Gao, Mei Feng, et al., includes contributions from the Peking University-Yunnan Baiyao International Medical Research Center and other institutions. The paper was published in the Cancer Cell journal on June 10, 2024, by Elsevier, and can be accessed at this link: https://doi.org/10.1016/j.ccell.2024.04.012.

Detailed Research Process

a. Research Process

The study assembled a cohort of 287 AM patients, with a core discovery cohort of 147 patients and two validation cohorts comprising 140 patients. Among these patients, 146 were diagnosed with AMIS and 141 with IAM. The research combined six omics datasets: whole-exome sequencing (WES), multi-region sequencing based on laser capture microdissection (LCM), bulk RNA sequencing (RNA-Seq), single-cell RNA sequencing (scRNA-Seq), spatial transcriptomics sequencing, and co-detection index (CODEX) along with immunohistochemistry (IHC) datasets.

Specifically, the study involved the following main steps: 1. Assembled a cohort of 287 patients with acral melanoma. 2. Completed integrated analysis of six omics datasets, including WES, LCM, and multi-region sequencing. 3. Separated matched and highly purified tumor samples via LCM for genomic characterization. 4. Conducted single-cell level analysis of different cell populations using scRNA-Seq. 5. Performed spatial transcriptomic sequencing to explore the spatial distribution and interactions between tumor cells and TME components.

b. Results of Main Findings

1. Genomic Characteristics Comparison between In Situ and Invasive Acral Melanoma:

   • IAM samples had a higher proportion of subclonal mutations, indicating a higher degree of intratumor heterogeneity (ITH).
   • WES results showed significantly higher mutation frequencies of four driver genes (NRAS, KRAS, NF1, and KIT) in IAM samples, termed as “invasive driver genes.”

2. In Vivo and Ex Vivo Experiments:

   • Experiments demonstrated that APOE+/CD163+ macrophages promoted epithelial-mesenchymal transition (EMT) in tumor cells through the IGF1-IGF1R pathway.
   • Expression of APOE and CD163 served as prognostic biomarkers in IAM patients.

3. Spatial Transcriptomics Analysis:

   • Spatial transcriptomics revealed direct contact and close interaction between APOE+/CD163+ macrophages and EMT-high tumor cells.

c. Scientific and Application Value of the Research

This study has significant clinical value for the early detection and treatment of acral melanoma. By revealing critical molecular determinants during tumor evolution and their interactions with the TME, the research offers new insights into the molecular typing and invasive patterns of AM.

It indicates that APOE and CD163 expressions can serve as prognostic biomarkers for IAM patients, and APOE+/CD163+ macrophages promote EMT in tumor cells through the IGF1-IGF1R pathway. These findings provide new potential targets for targeted therapy.

d. Research Highlights

• Discovery of Invasive Driver Genes: Identification of four driver genes (NRAS, KRAS, NF1, and KIT) and validation of their functions.
• Subclonal Evolution Patterns: Revealed significant genomic instability and a high proportion of subclonal mutations in IAM.
• New Applications of Spatial Transcriptomics: Demonstrated clear spatial distribution and interactions with TME components, providing a template for future research.

e. Other Valuable Information

The study discussed the importance of early diagnosis in improving patient survival and suggested methods for distinguishing highly invasive AMIS from indolent AMIS through routine pathological examinations or genetic screening. It also recommended regular follow-up for AMIS patients with high invasive potential after surgical resection to monitor disease progression.

Conclusion

By integrating multiple omics datasets, this study elucidated the evolutionary dynamics of acral melanoma from the in situ stage to the invasive stage and the tumor-immune interactions, highlighting the crucial role of APOE+/CD163+ macrophages in promoting tumor EMT and their prognostic significance. These findings provide new avenues and directions for early detection and personalized treatment of acral melanoma.