From Primary Tumor to Metastatic Niche: Microenvironmental Determinants of Metastasis in Gastrointestinal Cancers

Metastasis remains the principal cause of death in gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, pancreatic, and hepatobiliary malignancies. Despite advances in surgery, systemic therapy, and immunotherapy, a large proportion of patients still relapse at distant sites — most often the liver and peritoneum. Increasing evidence indicates that the outcome of this process is not decided by tumor-cell-intrinsic properties alone. The microenvironment at both ends of the journey — the primary tumor and the distant organ that receives the disseminating cells — actively shapes which cells leave, which survive in circulation, and which succeed in colonizing a new site.Within the primary tumor, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, endothelial and neural components, extracellular matrix stiffness, hypoxia, and metabolic stress cooperate to license invasion and immune escape. In parallel, tumor-derived extracellular vesicles, cytokines, and metabolites condition distant organs before the arrival of tumor cells, establishing pre-metastatic niches with altered immune composition, vascular permeability, and matrix architecture. The gut microbiota and its metabolites add a further layer of regulation that is particularly relevant to GI tumors. How these compartments communicate, and how that communication can be interrupted therapeutically, remains incompletely understood.The goal of this Research Topic is to bring together mechanistic, translational, and clinically oriented work that clarifies the microenvironmental determinants of metastasis across the full trajectory — from the primary lesion, through dissemination, to colonization of the metastatic niche — and that translates these insights into biomarkers and treatment strategies for patients with GI cancers.We welcome Original Research, Review, Mini Review, Systematic Review, Methods, Perspective, Opinion, Case Report, and Clinical Trial articles addressing, but not limited to, the following themes:• Stromal and immune remodeling of the primary GI tumor microenvironment and its link to invasion and dissemination• Cancer-associated fibroblast heterogeneity, matrix remodeling, and mechanical cues driving metastatic competence• Formation and regulation of organ-specific pre-metastatic niches, with emphasis on liver and peritoneal metastasis• Extracellular vesicles, secreted factors, and metabolic crosstalk between tumor and distant organs• Metabolic reprogramming, hypoxia, and nutrient competition in metastatic colonization• Gut microbiota and microbial metabolites as modifiers of the metastatic microenvironment• Perineural and lymphovascular invasion, angiogenesis, and vascular niche biology• Dormancy, immune surveillance, and reactivation of disseminated tumor cells• Spatial transcriptomics, single-cell multi-omics, and advanced imaging applied to matched primary and metastatic tissue• Patient-derived organoids, ex vivo, and in vivo models that recapitulate niche-tumor interactions• Microenvironment-informed biomarkers of metastatic risk and response to immunotherapy or targeted therapy• Therapeutic strategies targeting the stromal, immune, or metabolic compartment to prevent or treat metastasisPlease note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal. Topic editors: Haruto Nishida, Jie-ying Liang, Linhui Wang Source: https://www.frontiersin.org/research-topics/86244/from-primary-tumor-to-metastatic-niche-microenvironmental-determinants-of-metastasis-in-gastrointestinal-cancers