Molecular Adaptation Mechanisms Driving Therapy Resistance in Gastrointestinal Malignancies: A New Research Initiative
核心洞察
Gastrointestinal malignancies remain among the leading causes of cancer-related mortality worldwide, with therapeutic resistance posing the greatest challenge to durable clinical responses.
Resistance is increasingly understood to be driven not only by genetic mutations but also by dynamic molecular adaptation processes including metabolic rewiring, epigenetic remodeling, and immune evasion.
A new Frontiers Research Topic aims to advance understanding of how GI tumors adapt to therapeutic pressure, highlighting emerging technologies such as single-cell sequencing, spatial transcriptomics, and organoid models.
Despite substantial advances in targeted therapy, immunotherapy, antibody-drug conjugates, and precision oncology, gastrointestinal malignancies continue to rank among the leading causes of cancer-related mortality worldwide. Therapeutic resistance remains one of the greatest challenges limiting durable clinical responses and long-term patient survival across gastric cancer (搜索), colorectal cancer (搜索), pancreatic cancer (搜索), liver cancer (搜索), and esophageal cancer (搜索).
A newly launched Research Topic in Frontiers, titled "Molecular Adaptation Mechanisms Driving Therapy Resistance in Gastrointestinal Malignancies," aims to provide a comprehensive platform for mechanistic, translational, and clinical studies investigating the molecular underpinnings of treatment failure in these diseases.
Beyond Genetic Mutations: The Dynamic Nature of Resistance
Increasing evidence suggests that resistance is not solely driven by genetic mutations, but also by dynamic molecular adaptation processes that enable tumor cells to survive under therapeutic pressure. Recent studies have highlighted the critical roles of metabolic rewiring, epigenetic remodeling, tumor microenvironment interactions, immune evasion, stress-response signaling, and cellular plasticity in shaping therapy resistance across gastrointestinal cancers.
"Resistance is not solely driven by genetic mutations, but also by dynamic molecular adaptation processes that enable tumor cells to survive under therapeutic pressure," the Research Topic editors note, underscoring the paradigm shift in how the field conceptualizes treatment failure.
Emerging Technologies Illuminate Resistance Mechanisms
In parallel with these mechanistic insights, rapidly evolving technologies are providing new opportunities to better understand resistance evolution and identify novel therapeutic vulnerabilities. The Research Topic highlights the transformative potential of single-cell sequencing, spatial transcriptomics, organoid models, and multi-omic profiling in dissecting the complex biology of drug-tolerant states.
Of particular interest are drug-tolerant persister (DTP) cells and senescence-like persister cells in gastric cancer (搜索), including their role in therapy resistance, tumor recurrence, and disease progression. These cellular populations are increasingly recognized as reservoirs for eventual relapse.
A Multidisciplinary Call for Contributions
The Research Topic welcomes Original Research, Reviews, Mini Reviews, and Perspective articles addressing a broad spectrum of themes, including molecular mechanisms underlying therapeutic resistance, metabolic rewiring and redox adaptation during therapeutic stress, tumor microenvironment remodeling and immune escape mechanisms, and epigenetic regulation with cellular plasticity and signaling pathway reprogramming.
Additional areas of focus include resistance to immunotherapy, targeted therapy, chemotherapy, radiotherapy, and combination therapies, as well as biomarker discovery and prediction of therapeutic response. The editors also seek contributions on novel therapeutic strategies targeting adaptive signaling networks in gastrointestinal malignancies.
The initiative explicitly notes that manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases without accompanying validation—whether through independent clinical or patient cohorts, or biological validation in vitro or in vivo—are not suitable for publication.
Toward Precision Oncology for GI Malignancies
The overarching goal of this Research Topic is to advance understanding of how gastrointestinal tumors dynamically adapt to therapeutic pressure and develop resistance to current treatment strategies. By bringing together multidisciplinary perspectives, the editors hope to facilitate the development of more effective precision oncology approaches for gastrointestinal malignancies, ultimately translating mechanistic insights into clinical strategies that can overcome resistance and improve patient outcomes.