Open research questions in Cancer Cells and Metastasis

What the literature leaves open

• The independent influence of ECM aging on tumor growth is not well understood. The role of LOX in breast cancer progression requires further investigation.

  Transcriptomic insights into age-associated extracellular matrix promotion of breast cancer · 2026 · DOI

• a hybrid approach that pairs the predictive power of dense, continuous representations with the biological interpretability at the heart of CANVAS, - prospective, controlled validation, - exploring nuanced tissue patterns not captured by the current targets

  Reading tumor ecosystems from routine histology · 2026 · DOI

• The high cost and technical complexity of spatial proteomics and transcriptomics have impeded their adoption in routine clinical practice. Prior efforts to predict molecular markers from H&E images have been hampered by limited availability of experimental data and technical variability between samples.

  Reading tumor ecosystems from routine histology · 2026 · DOI

• The mechanisms involved in EMT are complex and not fully understood. There is a need to study the pattern of signaling transduction and molecular mechanisms involved in EMT. The paper identifies a gap in understanding the role of extracellular signals and autocrine factors that activate EMT.

  Role of epithelial-mesenchymal transition (EMT) in malignancies: current status and future prospects · 2026 · DOI

• Achieving a balance between sustaining viability and preserving tumor-relevant function in precision-cut tumor slices. Standardized cryopreservation and thawing protocols for precision-cut tumor slices remain underdeveloped. Maintaining the protumorigenic microenvironment in precision-cut tumor slices.

  Precision-cut tumor slices: a biomimetic tool for accelerating oncological development from basic research to clinical translation · 2026 · DOI

• Investigating the roles of gene damage and mutation in tumorigenesis, - Developing nonpharmacological therapeutic methods, - Improving cryopreservation and thawing protocols for PCTS, - Exploring the potential of PCTS in clinical translation

  Precision-cut tumor slices: a biomimetic tool for accelerating oncological development from basic research to clinical translation · 2026 · DOI

• Limited number of donors, - Ethical challenges, - Limited accessibility to laboratory plans and reports, - Need for continuous education on animal welfare, - Difficulty in differentiating enteroendocrine cells

  Adult Animal Stem Cell-Derived Organoids in Biomedical Research and the One Health Paradigm · 2024 · DOI

• Investigating host-pathogen interactions using animal-derived organoids, - Developing organoids from additional species, - Improving the differentiation of enteroendocrine cells, - Addressing ethical challenges related to organoid technology

  Adult Animal Stem Cell-Derived Organoids in Biomedical Research and the One Health Paradigm · 2024 · DOI

• Metastasis is responsible for the vast majority of cancer‐related deaths, yet organ selectivity and the fate of disseminated cancer cells remain incompletely understood.

  Metastatic niche shaped by host factors influences disseminated cancer cell fate · 2026 · DOI

• Metastatic cancer cells must adapt to the physical properties of distant tissues, yet the consequences of such mechanical adaptation for immune surveillance remain poorly understood.

  A Stiff Achilles’ Heel: How Tumor Mechanics Shape Metastatic Vulnerability · 2026 · DOI

• However, the relationship among these two stem cell populations and differentiated cells remains to be clarified.

  Fetal reversion from diverse lineages sustains the intestinal stem cell pool and confers stress resilience · 2026 · DOI

• We provide quantitative benchmarking of success rates, immune cell persistence, and predictive accuracy, and discuss contradictory findings, reproducibility challenges, and technical barriers that limit clinical translation.

  Tumor organoid-immune cell co-culture systems for precision oncology · 2026 · DOI

• Mechanisms explaining how the microvasculature responds to ECM alterations remain unknown.

  Perivascular cells function as key mediators of mechanical and structural changes in vascular capillaries · 2025 · DOI

• Despite their critical role, the biological differences between single CTCs and CTC clusters remain unclear.

  Src/FN1 pathway activation drives tumor cell cluster formation and metastasis in lung cancer: A promising therapeutic target · 2025 · DOI

• High‐resolution knowledge of the transcriptional programs underlying the role of CSC niche in driving tumor stemness and progression is still lacking.

  Dissecting the Spatial and Single‐Cell Transcriptomic Architecture of Cancer Stem Cell Niche Driving Tumor Progression in Gastric Cancer · 2025 · DOI

• Circulating tumor cells (CTCs) are pivotal biomarkers in tumor metastasis, however, the underlying molecular mechanism of CTCs behavioral heterogeneity during metastasis remains unexplored.

  Linking Metastatic Behavior and Metabolic Heterogeneity of Circulating Tumor Cells at Single‐Cell Level Using an Integrative Microfluidic System · 2025 · DOI

• Although emerging evidence suggests that Tensin-1 (TNS1) contributes to tumor metastasis, its precise function in EMT during lung cancer progression and the underlying mechanisms remain unclear.

  A positive feedback loop between TNS1 and ZEB1 promotes TGFβ-induced epithelial-to-mesenchymal transition in lung cancer · 2025 · DOI

• Introduction The role of cancer-associated fibroblasts (CAFs) in the progression, therapeutic resistance, and metastasis of castration-resistant prostate cancer (CRPC) remains incompletely understood.

  CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer · 2025 · DOI

• Background Colorectal cancer (CRC) remains a leading cause of cancer mortality, with liver metastasis being the principal determinant of poor prognosis, but the spatial mechanisms orchestrating metastatic niches remain elusive.

  A spatially resolved single-cell landscape of colorectal cancer liver metastasis reveals a stromal-tumor glycolytic signaling interaction · 2025 · DOI

• The use of canine organoids in drug testing and disease modeling has been limited by the number of models as well as the depth of characterization.

  Establishment and transcriptomic characterization of canine organoids from multiple tissues · 2025 · DOI

• Only a few studies have reported on the role of BAP31 in activating invasion and metastasis.

  A five-plex Hepatic Oncochip reveals EMT triplet correlated with BAP31 in liver cancer · 2025 · DOI

• Few studies have investigated several EMT markers in a large number of biopsies, making it difficult to identify the occurrence of EMT based on a single marker alone (11).

  A five-plex Hepatic Oncochip reveals EMT triplet correlated with BAP31 in liver cancer · 2025 · DOI

• By bridging existing gaps in knowledge and fostering advancements in personalized medicine, this review aims to guide the development of more effective cancer treatment strategies, ultimately improving patient outcomes.

  Deciphering the Role of Cancer Stem Cells: Drivers of Tumor Evolution, Therapeutic Resistance, and Precision Medicine Strategies · 2025 · DOI

• Abstract Tumor tissues consist of heterogeneous cells that originate from stem cells; however, their cell fate determination program remains incompletely understood.

  Paneth-like cells produced from OLFM4+ stem cells support OLFM4+ stem cell growth in advanced colorectal cancer · 2024 · DOI

• However, it remains unknown how the cells employ FGF signaling to convert their behaviors to achieve the recursive branching processes.

  ERK-mediated curvature feedback regulates branching morphogenesis in lung epithelial tissue · 2024 · DOI

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
• Genes that mediate breast cancer metastasis to lung · Nature · 2005 · 2,487 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
• Patient-derived tumor organoids: advances, applications, and future directions in biomedical research · Frontiers in Medicine · 2026
• Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition · Cell · 2026
• Collective fate decisions and cell rearrangements underlie gastruloid symmetry breaking · bioRxiv · 2026
• Fetal reversion from diverse lineages sustains the intestinal stem cell pool and confers stress resilience · Communications Biology · 2026
• A 3D morphogenetic blueprint for metastatic outgrowth in breast cancer · Cell · 2026
• Partial-EMT in oral squamous cell carcinoma: molecular circuitry and clinical translation · International Journal of Oral Science · 2026
• A tumour-derived organoid biobank maps cancer gene dependencies · Nature · 2026
• NRF1 Induces ApoEhigh Cancer-Associated Fibroblasts to Promote Stemness of Renal Cell Carcinoma · Cancer Research · 2026

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