Stress Signals in the Tumor Ecosystem: Extracellular Communication, Metabolic Adaptation, and Genome Stability in Cancer Cell Plasticity and Therapy Resistance

Abstract:Tumors are dynamic ecosystems in which cancer cells continuously receive, interpret, and propagate signals from their microenvironment. Among the most consequential of these are stress-driven signals generated by chronic hypoxia, inflammatory mediators, and metabolic pressure that collectively reshape cancer cell identity in ways that promote disease progression and treatment failure.Extracellular vesicles have emerged as key vehicles for intercellular communication within this ecosystem. By carrying bioactive cargo including proteins, lipids, and nucleic acids between cancer cells, immune populations, and stromal components, EVs actively reprogram recipient cells toward stem-like, plastic states that resist both microenvironmental pressure and therapeutic intervention. At the same time, hypoxia and nutrient stress activate energy-sensing pathways such as AMPK, coordinate stress-activated kinase cascades including SAPK/JNK, and trigger cytoprotective autophagy, collectively enabling cancer cells to survive and adapt under conditions that would otherwise suppress proliferation.At the genomic level, these environmental pressures impose a further layer of instability. Telomere dysfunction arising from replicative stress amplified by microenvironmental damage alters cell fate decisions, drives chromosomal rearrangement, and may facilitate both senescence escape and tumorigenic progression. The mechanistic links between extracellular communication, stress-activated metabolism, and genome integrity represent an underexplored but critical axis of cancer cell plasticity.This Research Topic invites original research, reviews, and perspectives that examine how extracellular signalling, metabolic stress sensing, and genomic stability collectively shape cancer cell plasticity, stemness acquisition, and therapy resistance. We particularly welcome mechanistic and translational studies using cancer cell models, patient-derived systems, organoids, co-culture platforms, and in vivo models.Scope:This Research Topic sits at the intersection of tumor microenvironment biology, cancer cell-intrinsic reprogramming, and therapeutic vulnerability. Contributions of interest include:- EV-mediated intercellular communication in the tumor microenvironment: cargo composition, transfer mechanisms, and functional impact on cancer cell identity and plasticity- EVs as drivers of cancer cell transcriptional reprogramming, stemness acquisition, and phenotypic state transitions- Hypoxia-regulated pathways including HIF, AMPK, and stress-activated kinases in cancer cell metabolic adaptation, survival, and therapy resistance- Cytoprotective autophagy as a resistance mechanism under microenvironmental and therapeutic stress- Telomere dynamics and telomerase activity in cancer cells responding to microenvironmental pressure: contributions to genome instability and cell fate- DNA replication stress and telomere attrition as modulators of cancer cell plasticity and malignant progression- Inflammatory regulation of extracellular signalling and its downstream effects on cancer cell identity and treatment response- Cancer stem cell maintenance, self-renewal, and therapy evasion in the context of a stressed tumor ecosystem- Translational studies identifying biomarkers or therapeutic targets within these interconnected pathways- Studies using cell culture models, in vivo systems, patient-derived xenografts, organoids, or co-culture platforms to validate mechanistic findingsStudies that are purely descriptive or consist only of bioinformatic analyses without experimental validation and mechanistic insight would fall outside the scope of this collection. Topic editors: Alessandro Sarcinella, Keith R. Laderoute, Monika Baj-Krzyworzeka Source: https://www.frontiersin.org/research-topics/83458/stress-signals-in-the-tumor-ecosystem-extracellular-communication-metabolic-adaptation-and-genome-stability-in-cancer-cell-plasticity-and-therapy-resistance