Metabolic analysis and identification of potential biomarkers of early-stage melanoma lung metastasis

Abstract

Tumor cells exhibit a notable ability to adapt to constantly changing microenvironments and possess distinct metabolic traits during metastasis. This study aims to establish a melanoma lung metastasis model in mice to elucidate the metabolic mechanisms involved in early-stage metastasis prior to treatment. The male C57BL/6 mice are divided into five groups based on time intervals of 6, 24, 72, and 120 h post-injection (SKCM-M groups) of melanoma cells, as well as a normal control group (NOR group). Our results demonstrate that platelet activation mainly occurs in the initial phases of metastasis to help tumor cells survive. NMR-based metabolomics analysis of mouse lung tissues identifies distinct metabolites and pathways associated with early-stage metastasis, revealing significant alterations in energy and amino acid metabolism during tumor progression. Further analysis indicates that methylxanthine and allantoin could serve as potential biomarkers for monitoring the early progression of tumor metastasis in cancer patients, providing novel insights into early diagnostic strategies for lung metastasis.

1. Introduction

Tumor metastasis is an extraordinarily complex and multifactorial phenomenon characterized by metabolic alterations across multiple organs and is intricately intertwined with diverse biological processes. Approximately 90% of cancer-related fatalities are caused by metastasis [1], with approximately 20% of cases presenting with distant metastasis at the time of clinical diagnosis [2]. Metastasis progression is intricate and comprises multiple steps, which are dependent not only on the intrinsic characteristics of tumor cells but also on their interaction with the surrounding microenvironment [3,4]. This interaction profoundly influences cancer progression and metastasis.

The viability of tumor cells in the bloodstream during metastasis is crucial, with tumor-educated platelets (TEPs) identified as functional cells by exhibiting a distinctive tumor-promoting phenotype. When platelets are triggered by tumor cells, they become activated and form a protective barrier around the tumor cells, helping tumor cells evade the host’s immune response [5]. Scientists postulate that tumor cell-induced platelet activation is a pivotal factor in the process of hematogenous metastasis in cancer [6,7]. One mechanism involves the interaction between the podoplanin protein (PDPN) on the surfaces of various tumor cells and the C-type lectin-like receptor 2 (CLEC-2) on platelets, which activates platelets and promotes tumor metastasis [8–10].

To survive and thrive in new organs, the metabolic characteristics of metastatic cells, including transcriptional regulation, translation, and enzyme utilization, are continually adjusted [11]. Additionally, many secondary tumors develop metabolic profiles distinct from those of primary tumors, enhancing their adaptation to the new environment [12]. Metabolism serves as the pivotal hub of cellular existence, intricately connecting various elements such as the microenvironment, phenotype, signal transduction, and genetic background [13,14]. Therefore, metabolic profiling analysis can provide deeper insights into the mechanisms and pathways underlying disease progression [15]. Metabolomics, a valuable tool for examining biological metabolic changes, offers theoretical and technical support for the early detection and treatment of diseases.