Open research questions in Cancer Cells and Metastasis
776 gap statements mined from Cancer Cells and Metastasis papers in our 7.9M-paper local library, which holds 2,532 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
Prospective, biomarker-driven interventional trials are warranted to determine whether early CTC changes can be used to guide treatment decisions in eribulin-treated MBC.
Efficacy, safety and circulating tumor cell dynamics in patients treated with Eribulin for HER2-negative advanced breast cancer – results from the phase II DETECT IVb trial · 2026 · DOISeveral limitations of this study have to be considered. The interpretation of longitudinal CTC analyses is also limited by the variable timing of follow-up CTC assessments and the lack of correlation with radiological response.
Efficacy, safety and circulating tumor cell dynamics in patients treated with Eribulin for HER2-negative advanced breast cancer – results from the phase II DETECT IVb trial · 2026 · DOIThe reason for this finding remains unclear, as Snail is a rather well-known EMT transcription factor. The reasons for these differences remain unknown.
Zeb1 Is a Determinant of EMT in Human MDA-MB-231 Breast Cancer Cells and M13-MDA231 Tumor Hybrids · 2026 · DOICoupling AI predictions with metabolomics and high-throughput phenotypic screens will allow prioritization of understudied chemotypes for focused validation. Robust genetic validation of targets in physiologically relevant models is essential: CRISPR-based functional genomics can identify CSC dependencies, validate phytochemical targets, and reveal mechanisms of resistance or compensatory signaling.
Targeting Cancer Stem Cells with Phytochemicals: Molecular Mechanisms and Therapeutic Potential · 2026 · DOIFurther studies are warranted to validate its clinical performance and demonstrate utility in real-world applications, including therapeutic response monitoring, relapse risk assessment, and biomarker identification for targeted and immunotherapies—ultimately contributing to improved survival outcomes in NSCLC and other solid tumor cancers.
Evaluation of the Cellsway Microfluidic CTC Enrichment and Identification Platform for CTC Detection in Metastatic NSCLC · 2026 · DOIThe model was conceived to address a major limitation of conventional subcutaneous patient-derived xenografts. Most published studies relied on established tumor cell lines rather than patient-derived material; subserosal implantation predominated; engraftment rates varied widely, and several studies did not comprehensively address key criteria for model validation.
Development of an Orthotopic Patient-Derived Xenograft Model of Gastro-Esophageal Adenocarcinoma: A Single-Lineage Pilot Study · 2026 · DOIInstead, TGF-β signaling is required under these conditions, as pathway inhibition attenuates immune-driven morphogenesis whereas exogenous ligand is insufficient.
Immune-epithelial interactions orchestrate stem-cell niche formation and morphogenesis requiring TGF-β signaling · 2026 · DOIThe need to distinguish between cause and effect in the molecular changes associated with resistance. The challenge of translating findings into therapeutic applications while ensuring normal-stem-cell and long-term safety.
By standardizing protocols and establishing regional biobanks, organoids could be shared across institutions, reducing the need for each lab to develop its own models from scratch. Additionally, open-source microfluidics and 3D-bioprinted scaffolds are being explored to produce CRC-on-a-chip systems using affordable materials.
Exploring Experimental Models of Colorectal Cancer: A Critical Appraisal from 2D Cell Systems to Organoids, Humanized Mouse Avatars, Organ-on-Chip, CRISPR Engineering, and AI-Driven Platforms—Challenges and Opportunities for Translational Precision Oncology · 2025 · DOIChallenges remain, including the standardization of protocols, scalability of 3D systems, and ensuring robust clinical validation of these models. Future research should focus on addressing these limitations through advancements in synthetic matrices, real-time monitoring technologies, and modular microfluidic designs.
The Evolution of Anticancer 3D In Vitro Models: The Potential Role of Machine Learning and AI in the Next Generation of Animal-Free Experiments · 2025 · DOIHowever, the in vitro-acquired radioresistance of HNSCC cell lines has not been widely studied. However, there remains insufficient evidence to justify the inclusion of IL-6/IL-6R-targeted monotherapy as a first-line treatment for any solid malignancy.
Targeting Fibroblast-Derived Interleukin 6: A Strategy to Overcome Epithelial-Mesenchymal Transition and Radioresistance in Head and Neck Cancer · 2025 · DOIFuture studies will address these limitations by validating the model in syngeneic or humanized immune-competent mouse systems, incorporating longer-term monitoring, and expanding therapeutic testing to include immunotherapeutic agents and combination regimens. Nevertheless, certain limitations of the current study should be acknowledged.
Establishment of an Orthotopic and Metastatic Colorectal Cancer Mouse Model Using a Tissue Adhesive-Based Implantation Method · 2025 · DOIIn the coming years, we need to unify all these open questions so that we can bring the myriad streams of our research back to the bed of a larger river.
Second, technical challenges, including the variability of matrix scaffolds and the lack of standardized cutoff values for defining drug resistance, hinder reproducibility and rigorous clinical validation.
Modeling Drug and Radiation Resistance with Patient-Derived Organoids: Recent Progress, Unmet Needs, and Future Directions for Lung Cancer · 2025 · DOISince dormant cells seem to share common signaling pathways with cancer stem cells, possible biomarkers of these stem cells could be studied, and some method to differentiate them from dormant cells could be sought. After reviewing the current literature, few studies have determined the signaling pathways involved in inducing cell dormancy.
Anti-EMT therapy could sensitize tumors to immunotherapy, highlighting the importance of further research into EMT’s role in tumor development to develop improved treatments and enhance cancer outcomes.
Future research should focus on unveiling new molecular targets and developing therapies that prevent or reverse resistance, ensuring the long-term efficacy of CRC treatments.
Future investigations need to focus on designing trials that assess medications that are potentially beneficial for both the initial and later stages of CRC management. The shortfall in exacting preclinical frameworks that encompass both inherent and environmental tumor properties, including subsets of CSCs, the tumor’s structural framework, and the TME, remains a substantial scientific hurdle.
Particularly, spheroids can aid in the testing of potential treatments through the evaluation of drug penetration and accumulation. Spheroid characterization is an essential step in cancer research to establish a reliable model.
Mimicking the Complexity of Solid Tumors: How Spheroids Could Advance Cancer Preclinical Transformative Approaches · 2025 · DOIThe intestine is constantly exposed to various mechanical forces that influence the behavior and homeostasis of intestinal epithelial cells, including shear stress, stiffness, compression, and stretching. These forces play crucial roles in maintaining intestinal integrity by regulating the proliferation and differentiation of ISCs via mechanotransduction signaling pathways.
In recent years, cell technologies have been developed significantly, allowing us to study various aspects of cellular existence, starting from monoclonal cultures, which provide the opportunity to deeply investigate specific mechanisms, and ending with the creation of organs-on-a-chip, which reproduce the influence of the microenvironment.
Further study on the independent contribution of individual medium components, - Investigation of the effects of different dissociation strategies on organoid…
An empirically refined workflow for generating patient-derived organoids from epithelial ovarian cancer · 2026 · DOIThe study used existing datasets and did not collect new data, - The study focused on a specific type of cancer (colorectal cancer), - The study used a limited number of cell lines (HCT-8 and HCT-15) for functional…
COL8A1-positive cancer-associated fibroblasts are drivers of 5-fluorouracil resistance in colorectal cancer · 2026 · DOIInvestigating the mechanisms of COL8A1⁺Fibs in promoting EMT pathway activation, - Exploring the potential of targeting COL8A1⁺Fibs as a therapeutic strategy for overcoming 5-FU resistance, - Studying the role of COL8A1⁺Fibs in other types…
COL8A1-positive cancer-associated fibroblasts are drivers of 5-fluorouracil resistance in colorectal cancer · 2026 · DOILongitudinal studies to support regulatory-state heterogeneity at relapse, - Separate measures of target engagement, cell-state redistribution, and sustained loss of tumor-propagating capacity, - Normal-stem-cell and long-term safety…
Most-cited papers in Cancer Cells and Metastasis
- On the Origin of Cancer Cells · Science · 1956 · 11,495 citations
- Stem cells, cancer, and cancer stem cells · Nature · 2001 · 7,629 citations
- A Perspective on Cancer Cell Metastasis · Science · 2011 · 4,078 citations
- Gain-of-Function Mutations of c- kit in Human Gastrointestinal Stromal Tumors · Science · 1998 · 3,616 citations
- Tumors: Wounds That Do Not Heal · New England Journal of Medicine · 1986 · 3,544 citations
- A human colon cancer cell capable of initiating tumour growth in immunodeficient mice · Nature · 2006 · 3,280 citations
- Identification and expansion of human colon-cancer-initiating cells · Nature · 2006 · 3,258 citations
- Next-generation characterization of the Cancer Cell Line Encyclopedia · Nature · 2019 · 3,172 citations
- Clonal evolution in cancer · Nature · 2012 · 2,838 citations
- The tumor microenvironment · Current Biology · 2020 · 2,592 citations
Most recent work
- Hallmarks of cancer—Then and now, and beyond · Cell · 2026
- Shifting paradigms in tissue stem cell biology: Insights from the intestine · Cell · 2026
- TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis · Nature Cancer · 2026
- Cancer stem cell-driven drug resistance in colorectal carcinoma: molecular aspects and therapeutic potentials · Molecular Cancer · 2026
- BPHL promotes TNBC stemness by resolving R-loops via POLR2A lactylation inhibition and BARD1-mediated ubiquitination · Cancer Letters · 2026
- Remodeling the tumor dormancy ecosystem to prevent recurrence and metastasis · Signal Transduction and Targeted Therapy · 2026
- Signaling pathways and targeted interventions for precancers · Signal Transduction and Targeted Therapy · 2026
- Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1 · Cell Reports · 2026
- Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts · Cancer Cell · 2026
- Patient-derived tumor organoids: advances, applications, and future directions in biomedical research · Frontiers in Medicine · 2026
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