An insight into cancer from biomolecular condensates

For decades, cancer research has focused on the dysregulation of various cellular pathways, including transcription, chromatin structure, proliferative signaling, RNA processing, and genomic integrity maintenance. These processes involve intricate spatial and temporal interactions among DNA, protein, and RNA molecules. Historically, research has provided a mechanistic understanding of these processes in both healthy and diseased states, leading to therapeutic hypotheses that have advanced medical research. However, recent studies have highlighted the role of biomolecular condensates—nonmembrane-bound organelles—in compartmentalizing and regulating these biological processes. These condensates, formed through phase separation, exhibit physicochemical properties that classical molecular biology does not fully anticipate. This novel insight has prompted further investigation into the role of biomolecular condensates in oncogenesis and potential therapeutic approaches for cancer patients.

Biomolecular Condensates in Cancer

Cancer Development and Metastasis

Cancer cells exhibit hallmark behaviors such as uncontrolled proliferation, evasion of growth suppression, resistance to cell death, genome instability, metastasis, and angiogenesis. These behaviors often result from mutations that disrupt the organization of domain structures within proteins, leading to the formation of abnormal biomolecular condensates. These condensates, in turn, play a crucial role in cellular functions, and their dysregulation can contribute to cancer progression. Research is increasingly focused on understanding whether mutations that lead to cancer are associated with the production and modulation of these condensates, which could have implications for cancer diagnosis and therapy.

The emergence of biomolecular condensates as critical players in cellular function underscores their potential role in cancer biology. These condensates are formed via liquid-liquid phase separation, allowing cells to organize biochemical reactions efficiently. In cancer, mutations in genes encoding proteins that form or regulate these condensates can lead to aberrant cell behavior. For instance, mutations in the gene encoding the RNA-binding protein FUS can result in the formation of abnormal condensates that disrupt cellular homeostasis and contribute to tumorigenesis​​.

Role in Proliferative Signaling

In healthy tissues, cell growth is tightly regulated. However, cancer cells override these controls, leading to excessive cell division. This is often due to mutations that activate receptor tyrosine kinases (RTKs) and downstream signaling pathways, such as the RAS pathway. In this context, biomolecular condensates play a role by compartmentalizing signaling molecules, thus regulating their activity. Disruptions in this process due to cancer-causing mutations can lead to uncontrolled cell proliferation.

The compartmentalization of signaling molecules within biomolecular condensates ensures the specificity and efficiency of signal transduction. For example, the formation of condensates involving proteins like KRAS and RAF allows for the localized activation of the MAPK signaling pathway, which is crucial for cell proliferation. Mutations that alter the dynamics of these condensates can lead to prolonged and uncontrolled signaling, promoting oncogenesis. Understanding the specific mechanisms by which these condensates regulate proliferative signaling pathways could provide novel therapeutic targets for inhibiting excessive cell growth in cancer​.

Evasion of Growth Suppression

Cancer cells evade growth suppression by altering endogenous tumor suppressor pathways. One key player is the speckle-type POZ protein (SPOP), which serves as a substrate adaptor for the cullin3-RING ubiquitin ligase complex. SPOP mutations, common in cancers such as breast and prostate cancer, disrupt its function, leading to the accumulation of tumor-promoting substrates. This highlights the importance of SPOP in tumor suppression and the potential therapeutic benefits of targeting biomolecular condensates involved in this pathway.

SPOP mutations often result in the mislocalization of the protein and its associated substrates, preventing the formation of functional ubiquitin ligase complexes. This failure leads to the stabilization of oncogenic factors that would otherwise be degraded. The study of SPOP and its role in the formation and regulation of biomolecular condensates is essential for developing strategies to restore its tumor-suppressive functions. By targeting the pathways involved in SPOP condensate formation, it may be possible to enhance the degradation of oncogenic substrates and inhibit cancer progression.

DNA Damage and Repair

Repair of Foci-Resistance from Cell Death

Apoptosis, a programmed cell death mechanism, is crucial for eliminating abnormal cells and preventing cancer. DNA damage, particularly double-stranded breaks, can trigger apoptosis. However, cancer cells often evade this fate by repairing DNA damage through the formation of membrane-free repair foci. These foci are facilitated by phase separation processes involving proteins such as PARP1 and FUS, which accumulate at sites of DNA damage and promote repair. Dysfunctions in these mechanisms can lead to disrupted apoptosis and cancer progression.

The formation of DNA repair foci is a dynamic process that involves the rapid assembly of repair proteins at sites of damage. Proteins such as 53BP1 and BRCA1 form condensates that facilitate the recruitment and activity of repair enzymes. When this process is dysregulated, cells may either fail to repair DNA properly or avoid apoptosis, leading to genomic instability and cancer. Therapeutic strategies that target the formation or function of DNA repair condensates could enhance the sensitivity of cancer cells to DNA-damaging agents and improve treatment outcomes.

Dysregulation of Condensates in Cancer

The dysregulation of biomolecular condensates is a hallmark of many cancers. Mutations that impair transcription, chromatin structure, and proliferative signaling often affect the formation and function of these condensates. This dysregulation can lead to the uncontrolled growth and survival of cancer cells. As research in this area advances, understanding the specific roles of different condensates in cancer could provide new avenues for diagnosis and treatment.

Biomolecular condensates are involved in various cellular processes, including the regulation of gene expression through transcriptional condensates. These condensates, such as those formed by transcription factors and coactivators, organize transcriptional machinery to enhance gene expression. In cancer, mutations that affect the proteins forming these condensates can lead to aberrant gene expression profiles that support tumor growth and survival. Targeting the specific components of transcriptional condensates that are dysregulated in cancer could offer a strategy to modulate gene expression and inhibit tumor progression​.

Therapeutic Implications

Analyzing the mechanisms behind common oncogenic events through the lens of condensate biology offers new insights into cancer treatment. By understanding how condensates regulate signaling pathways, transcription, and DNA repair, researchers can develop targeted therapies that disrupt these processes in cancer cells. This approach has the potential to enhance the specificity and efficacy of cancer treatments, offering hope for better management of the disease.

Therapeutic strategies that target biomolecular condensates may involve small molecules that disrupt the formation of these condensates or modulate their dynamics. For example, inhibitors of phase separation could prevent the formation of oncogenic condensates, while stabilizers of tumor-suppressive condensates could enhance their function. Additionally, targeting the specific protein-protein interactions within condensates could provide a high degree of specificity, minimizing off-target effects and improving the therapeutic index. Continued research into the molecular details of condensate biology will be essential for translating these insights into effective cancer therapies​.

Conclusions

The study of biomolecular condensates provides a new perspective on cancer biology. These nonmembrane-bound organelles play a crucial role in regulating various cellular processes, and their dysregulation is implicated in cancer development and progression. Continued research in this field holds promise for developing innovative therapeutic strategies that target these condensates, potentially improving outcomes for cancer patients. The integration of condensate biology into cancer research could lead to the discovery of novel biomarkers and therapeutic targets, ultimately advancing the fight against cancer.

Full text

https://www.xiahepublishing.com/2835-3315/CSP-2023-00018

The study was recently published in the Cancer Screening and Prevention.

Cancer Screening and Prevention (CSP) publishes high-quality research and review articles related to cancer screening and prevention. It aims to provide a platform for studies that develop innovative and creative strategies and precise models for screening, early detection, and prevention of various cancers. Studies on the integration of precision cancer prevention multiomics where cancer screening, early detection and prevention regimens can precisely reflect the risk of cancer from dissected genomic and environmental parameters are particularly welcome.

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