The Emerging Frontier of Phase Separation in Cancer Research: A Comprehensive Bibliometric Analysis

Cancer is a complex disease characterized by uncontrolled cell proliferation, making it one of the leading causes of human mortality. Despite extensive efforts to discover the underlying mechanisms behind cancer development, its pathogenesis remains a subject of intensive investigation. The complexity of cancer arises from the dynamic interplay of multiple gene-environment interactions. Recently, the concept of phase separation has made its mark in cancer research, greatly expanding our understanding of cancer biology.

Phase separation is a process that divides a homogeneous liquid solution of macromolecular components, such as proteins and nucleic acids, into two distinct phases: one enriched in macromolecules and the other depleted of the same constituents. These cellular structures formed by phase separation are known as membraneless organelles or biomolecular condensates. Unlike conventional membrane-bound organelles like the nucleus or mitochondria, these membraneless structures lack a lipid bilayer and are inherently unstable, capable of rapidly assembling or disassembling to meet the cell’s requirements. Biomolecular condensates enable the concentration of specific molecules in stable and well-defined structures, resulting in heightened biochemical reaction rates. For example, phase-separated droplets can enhance the RNA cleavage activity of hammerhead ribozymes by up to 70-fold.

To date, biomolecular condensates have been implicated in various cellular processes, including genomic regulation, signal transduction, and protein degradation. Interestingly, a reciprocal causation has been observed between abnormal phase separation and cancer development. Aberrations in phase separation are closely associated with several hallmark features of cancer, such as sustained proliferative signaling, angiogenesis induction, and resistance to cell death. Conversely, cancer-associated mutations can initiate the formation of new biomolecular condensates, which activate oncogenic pathways or drive oncogene transcription, promoting tumorigenesis. This intriguing link between phase separation and cancer has opened up new possibilities for developing drugs that target abnormal phase separation as a novel approach to cancer therapeutics.

Bibliometric analysis, a valuable tool for scientific researchers, allows for the comprehensive analysis of essential information such as authors, countries, institutions, journals, and citations in specific publications. This analysis not only highlights global research hotspots and features but also predicts future research directions. Despite the significance of phase separation in cancer research, a bibliometric analysis in this area had been lacking until now. In a new study published in the Frontiers in Oncology Journal by Dr. Mengzhu Li, Ms.  Yizhan Zhang, Dr.  Jiajun Zhao and led by Dr. Dawei Wang from Shandong University, presented a detailed analysis of the characteristics and trends in phase separation research in the context of cancer, shedding light on the current landscape and potential future directions.

The authors utilized the Web of Science Core Collection (WoSCC) to search for literature related to phase separation in cancer. The search criteria included specific topics related to cancer (neoplasia, tumor, malignancy) combined with keywords associated with phase separation (biomolecular condensate, membraneless organelle). The publication period ranged from January 1, 2009, to December 31, 2022, and only articles published in English were included. They employed GraphPad Prism 8 to visualize the number of papers published over time. Microsoft Excel 2021 was used to summarize the top 10 authors, organizations, countries, and the most cited articles. Additionally, VOSviewer and Citespace software were employed for bibliometric investigations, including co-authorship analysis, keyword burst analysis, and keyword co-occurrence analysis.

The authors analyzed 264 papers, comprising 137 articles and 127 reviews, related to phase separation in cancer. Notably, the first study addressing the biological function of phase separation in cancer emerged in 2016, and there has been a consistent increase in the number of publications and citations since then. The research trajectory can be divided into two phases: a slow and steady growth rate from 2016 to 2018 and a rapid expansion from 2018 to 2022, with each subsequent year seeing twice as many publications as the previous year. This surge in research activity suggests that phase separation’s role in cancer has gained substantial recognition and is poised for further development. The researchers found that distribution of these papers across research categories with biochemistry, molecular biology, and cell biology were predominant, accounting for 54.8% of the total publications. Other significant categories included Oncology, Chemistry Multidisciplinary, Multidisciplinary Sciences, Genetics Heredity, and Developmental Biology, underscoring the multidisciplinary nature of phase separation-related cancer research. The 264 papers analyzed by the authors accumulated a total of 6573 citations, with an average of 24.90 citations per paper. The ten most cited documents were predominantly reviews, with Alberti S.’s review ranking highest in terms of citations (290). Research articles authored by Bouchard JJ., Nair SJ., Klein IA., and Isoda T. also garnered substantial citations, ranging from 154 to 184.

According to the authors, the USA and China emerged as the leading countries in phase separation-related cancer research, collectively contributing to nearly three-quarters of all publications. However, while China had a significant number of publications, the average number of citations per paper from China was lower than that of Germany. In terms of organizations, the University of Chinese Academy of Sciences and the University of Texas System were the most prolific, with the former having the highest average citation per paper. Network analysis revealed the University of Chinese Academy of Sciences as the most active institution in collaborating with other organizations. Moreover, of the 137 journals that published papers on phase separation in cancer, the top ten journals with five or more publications were predominantly from the USA, England, and Switzerland. Molecular Cell emerged as the most productive journal, with the highest H-index, while Cell Journal had the highest total citations. Regarding authors, no single author dominated the field, and collaboration among research groups appeared limited. Among authors with at least two publications, they were distributed across 36 clusters, indicating a need for increased collaboration in this emerging research area.

The research team conducted keyword co-occurrence analysis and identified five clusters of research focus in phase separation-related cancer research. Cluster 1 centered on biomolecular condensates’ role in nuclear homeostasis, while Cluster 2 delved into the biological principles of anticancer drugs targeting phase separation processes. Cluster 3 explored the impact of DNA and RNA elements on phase separation-related diseases, and Cluster 4 highlighted the potential of phase separation in tumor microenvironment-related prognosis and therapy. Finally, Cluster 5 examined how cells responded to internal and external stimuli through phase separation. A keyword overlay visualization map depicted the evolution of research focus, suggesting that the keywords “tumor microenvironment,” “immunotherapy,” “prognosis,” “p53,” “cell death,” “intrinsically disordered region,” “immune response,” and “signal transduction” were likely to gain prominence as research hotspots in the future. Burst keyword analysis reinforced this notion, with keywords like “nuclear body,” “intrinsically disordered region,” “immune response,” and “signal transduction” identified as recent bursts, indicating emerging research trends.

In conclusion, the field of phase separation in cancer research is in a dynamic phase of growth and holds significant promise. The USA has emerged as the leading country in terms of productivity and influence, while China is also making substantial contributions. Collaboration among research groups and institutions is essential for further progress. The absence of a dominant author and the distributed authorship pattern highlight the need for interdisciplinary collaboration to fully grasp the complexities of phase separation in cancer biology. The emergence of keywords related to tumor microenvironment, immunotherapy, and signal transduction suggests that the field is progressing towards understanding phase separation’s role in the broader context of cancer biology and therapy. As phase separation in cancer research continues to evolve, it is poised to uncover novel therapeutic targets and strategies for cancer treatment. This comprehensive bibliometric analysis by Dr. Dawei Wang and colleagues at Shandong University provides valuable insights into the current state of the field, enabling researchers, institutions, and funding agencies to make informed decisions about future directions and collaborative opportunities in this exciting and rapidly expanding area of cancer research.