International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 293-304 http://medscipublisher.com/index.php/ijmms 299 5.4 Integration with other omics data Integrating spatial transcriptomics with other omics data, such as proteomics and single-cell RNA sequencing, provides a comprehensive view of the TME. Combined spatial transcriptomics and proteomics approaches enable the simultaneous analysis of RNA and protein expression, revealing the complex interactions between tumor cells and their microenvironment (Wang et al., 2021; Femel et al., 2023). This multi-omic integration enhances our understanding of tumor heterogeneity, immune cell infiltration, and the molecular mechanisms driving cancer progression and therapy resistance (Hu et al., 2022; Wang et al., 2021; Femel et al., 2023). 6 Insights into Tumor Microenvironment Dynamics 6.1 Spatial distribution of immune cells The spatial distribution of immune cells within the tumor microenvironment (TME) is a critical factor influencing cancer progression and therapeutic outcomes. In colorectal cancer (CRC), spatially resolved transcriptomic analyses have revealed distinct patterns of immune cell infiltration, particularly between mismatch repair deficient (MMRd) and proficient (MMRp) tumors. MMRd tumors exhibit higher cytolytic T cell infiltrates compared to MMRp tumors, indicating a more robust immune response (Price et al., 2022). Similarly, in triple-negative breast cancer (TNBC), spatial heterogeneity of immune markers such as CD3, CD4, CD8, CD20, and FoxP3 has been quantified, showing that the invasive front (IF) of tumors tends to have higher densities of immune cells compared to central tumor (CT) and normal tissue (N) regions (Mi et al., 2020). These findings underscore the importance of spatial organization in understanding immune dynamics within the TME. 6.2 Stromal and cancer cell interactions Stromal cells within the TME play a pivotal role in cancer progression through their interactions with cancer cells. Single-cell RNA sequencing of nasopharyngeal carcinoma (NPC) has identified multiple stromal subpopulations and their genetic profiles, highlighting the complex interplay between stromal and cancer cells (Gong et al., 2021). These interactions are further elucidated by 3D in vitro models, which mimic the TME and allow for the study of tumor-stroma interactions in a controlled environment (Rodrigues et al., 2021). The reprogramming of stromal cells by cancer cells through the secretion of cytokines and chemokines is a key mechanism that supports tumor survival and metastasis (Hinshaw and Shevde, 2019). Understanding these interactions is crucial for developing targeted therapies that disrupt the supportive role of stromal cells in cancer progression. 6.3 Vascular and hypoxic niches The TME is characterized by the presence of vascular and hypoxic niches, which contribute to tumor heterogeneity and resistance to therapy. In glioblastoma (GBM), spatial analysis has revealed that genetically distinct subpopulations of tumor cells are influenced by the hypoxic and angiogenic niches within the TME. These niches create selective pressures that drive the evolution of cancer cells, leading to the enrichment of specific clones with advantageous mutations (Onubogu et al., 2022). The presence of hypoxic regions within tumors is associated with poor prognosis and therapeutic resistance, making it a critical area of study for improving cancer treatment outcomes. 6.4 Evolution of TME during cancer progression The TME evolves dynamically during cancer progression, with significant implications for disease prognosis and treatment response. In colon cancer, a TME-related gene signature has been identified that correlates with patient survival and response to immunotherapy. This signature includes genes involved in immune-related pathways and highlights the prognostic value of TME composition (Chen et al., 2021). Additionally, the spatial organization of cells within the TME changes over time, as seen in CRC, where the distribution of immune and stromal cells shifts between MMRd and MMRp tumors (Price et al., 2022). These evolutionary changes in the TME underscore the need for longitudinal studies to fully understand the temporal dynamics of tumor-stroma interactions and their impact on cancer progression. By integrating spatial transcriptomics and single-cell sequencing technologies, researchers can gain deeper insights into the complex dynamics of the TME, paving the way for the development of more effective cancer therapies. The spatial distribution of immune cells, stromal and cancer cell interactions, vascular and hypoxic
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