The work, led by Professor Kwang-Hyun Cho of KAIST’s Department of Bio and Brain Engineering, introduces a technology called ROOT, short for “Revelation Of the Original circuit of irreversible Transition.” The framework is designed to locate the small set of regulatory interactions that keeps a cell locked in a changed state. By identifying and manipulating these circuits, the researchers demonstrated two conceptually different ways to control cellular memory: one that returns a cell to its former condition and another that removes the underlying mechanism that makes the change permanent.

Cells constantly alter their behavior in response to signals from their environment. A developing cell may receive instructions to specialize, an immune cell may mature into a functional subtype, or an epithelial cell may acquire the invasive properties associated with cancer. These transitions are often useful and necessary. Their persistence allows cells to maintain an identity after the initiating signal disappears. However, the same type of stability can become dangerous when a cell adopts a disease-associated state, such as the migratory and invasive phenotype generated during epithelial–mesenchymal transition, or EMT.

The molecular basis of this persistence lies in regulatory networks made from genes, proteins and signaling molecules. Within these networks, positive feedback loops allow molecules to reinforce their own activity indirectly. One molecule activates another, which activates a third, eventually returning to stimulate the original molecule. Such feedback can function like a biological latch: a temporary signal pushes the system across a threshold, after which the network continues operating without further outside instruction. According to the KAIST team, intracellular networks may contain more than a thousand interconnected positive feedback loops, making it extremely difficult to determine which ones are essential for maintaining an irreversible transition.

ROOT addresses this problem by converting molecular regulatory relationships into computational logic models. In these models, the activity of one component can be represented as dependent on the activity of others, much like logical conditions in a digital circuit. The researchers then analyzed the behavior of the resulting networks using systems biology methods, simulating how a cell responds to a stimulus, how the response persists after the stimulus is removed, and which interactions are indispensable for that persistence. This process allowed them to distinguish the extensive network surrounding an irreversible transition from the smaller group of interactions that actually sustains it.

The team describes that critical group as the “irreversibility kernel.” The kernel is not necessarily the largest or most obvious part of a regulatory network. Instead, it represents the causal circuitry that keeps the system from returning to its original state. Removing or altering the right components of the kernel can therefore have a much greater effect than broadly suppressing many unrelated molecules. The approach offers a way to move beyond correlation, where researchers observe that two molecules change together, toward a more mechanistic understanding of which molecular relationships are responsible for locking a cell into a particular fate.

The researchers proposed two control strategies based on the kernel. Resetting control returns a cell to its previous state while leaving its capacity for irreversible behavior intact. In the team’s analogy, this is like opening a locked door without dismantling the lock. A cell reset in this way could potentially be returned to an earlier identity, but it might still undergo another permanent transition if the relevant stimulus were applied again. Reversing control takes a more fundamental approach by disrupting the source of irreversibility itself. Once the responsible circuitry is disabled, the cell could, in principle, move between states more freely instead of automatically stabilizing in one direction.

To test the framework, the researchers applied ROOT to several biological systems. These included B-cell differentiation, EMT in lung cancer, and models of enterocyte and beta-cell differentiation constructed from single-cell transcriptome data. Single-cell transcriptomics measures gene activity in individual cells, allowing researchers to examine the regulatory programs associated with distinct cellular states rather than averaging signals across an entire tissue. In these models, ROOT identified causal circuits that corresponded with known determinants of cell fate and suggested more efficient strategies for resetting state transitions. The results indicate that the method can be applied not only to idealized computational networks but also to models grounded in experimental biological data.

The findings could influence how scientists think about diseases in which cells become abnormally fixed in a particular identity. Current cancer treatments often aim to kill malignant cells, while many approaches to age-related dysfunction focus on removing damaged cells or slowing the processes that produced them. A technology capable of pinpointing and manipulating the circuits that maintain abnormal states could eventually support a different strategy: restoring cells to a healthier condition. That possibility remains experimental, and computationally predicted control circuits would need to be validated in living cells, tissues and organisms before any therapeutic use could be considered. Still, by exposing the architecture of cellular irreversibility, ROOT provides a new map for investigating how biological systems remember change—and how those memories might one day be rewritten.

Subject of Research: Molecular circuits governing irreversible cellular state transitions and computational strategies for restoring or reversing those states.

Article Title: The structural origin of irreversible transitions in biological networks

News Publication Date: 21-Aug-2026

Web References: https://doi.org/10.1073/pnas.2600800123

References: Proceedings of the National Academy of Sciences; DOI: 10.1073/pnas.2600800123

Image Credits: KAIST

Keywords: ROOT framework, irreversible cell-state transitions, molecular regulatory networks, irreversibility kernel, systems biology, cancer research, aging research, epithelial–mesenchymal transition, cell differentiation, single-cell transcriptomics, cellular reprogramming

The fellowship arrives at a moment when cancer research is increasingly shaped by connections between disciplines once treated as separate. Cancer is not only a disease of uncontrolled cell division; it is also a disease of altered gene regulation, disrupted communication between organs, immune dysfunction, metabolic rewiring, and persistent interactions with infectious agents. The new projects reflect that broader view. Several researchers will study the regulatory architecture that determines which genes are active, while others will develop technologies for mapping cell surfaces, identify hidden immune targets, or investigate the molecular machinery that makes tumors vulnerable to treatment. Together, the projects illustrate how fundamental biology can generate new routes toward prevention, diagnosis, and therapy.

Nicholas Aboreden, PhD, a Robertson Foundation Fellow working with Kimberly Stegmaier, MD, at Dana-Farber Cancer Institute, will investigate the poorly understood regulatory elements known as silencers. Although only about 2 percent of the human genome encodes proteins, much of the remaining sequence controls when genes are activated or repressed. Cancer cells frequently exploit enhancers to increase the expression of growth-promoting genes, but the mechanisms by which they use silencers to maintain malignancy remain less clear. Aboreden will map the regulatory genome of an aggressive pediatric leukemia marked by widespread gene repression. By identifying silencer elements essential for the leukemia state, he hopes to uncover vulnerabilities that can be targeted without damaging normal cells. His work could also clarify how gene repression contributes to other tumor types.

At the California Institute of Technology, Timmerman Traverse Fellow Shihui Chen, PhD, will explore the relationship between embryonic development and cancer. During early embryogenesis, genetically identical cells acquire different identities through carefully coordinated changes in gene expression. Similar developmental programs can be reactivated in cancer, allowing malignant cells to adopt abnormal states and invade surrounding tissues. Working with Magdalena Zernicka-Goetz, PhD, Chen will use mouse embryos to study CARM1, a gene regulator frequently overexpressed in human tumors. She will determine how CARM1 influences early cell-fate decisions and how the same regulatory logic may be hijacked during cancer initiation. At The J. David Gladstone Institutes, Timmerman Traverse Fellow Stephanie A. Gaglione, PhD, will pursue another underexplored dimension of tumor biology: cryptic antigens. These immune targets arise from unusual or noncoding regions of viral and tumor genomes and may be shared among patients. With Alexander Marson, MD, PhD, Gaglione will profile the antigens displayed by virally driven cancers and identify those capable of stimulating tumor-specific T cells. The results could support engineered T-cell therapies and cancer vaccines directed at targets that conventional approaches overlook.

Several Fellows are developing tools to see cancer biology at unprecedented molecular resolution. Connie and Bob Lurie Fellow Yi Hua, PhD, working with Alice Y. Ting, PhD, at Stanford University School of Medicine, plans to create SortID, a labeling technology based on an engineered bacterial enzyme. The method is designed to rapidly label exposed protein residues on cell surfaces without requiring researchers to attach pre-existing molecular tags. Hua will use SortID to map the surface of SLAMF7, a protein already considered an important therapeutic target in multiple myeloma. A detailed map of the protein’s interactions could reveal how tumor cells communicate with immune cells and identify opportunities for more selective immunotherapies. At Stanford, Lurie Fellow Zhuoran Li, PhD, will examine a different communication system: peptide hormones produced by the brain. Computational analyses suggest that the brain generates many previously unrecognized peptides, but their biological functions remain unknown. Working with Katrin J. Svensson, PhD, Li will identify these signals and determine how they influence appetite and whole-body metabolism, potentially revealing brain–tumor connections relevant to the well-being of cancer patients.

Other projects focus on the molecular systems that determine whether cells survive stress or become malignant. Devon Jeltema, PhD, at the University of California, Berkeley, will study how PARP enzymes modify RNA. PARPs are best known for chemically modifying proteins involved in DNA repair and cellular stress responses, and several PARP inhibitors are already used in cancer treatment. Jeltema’s research will investigate whether RNA modification represents an additional layer of immune defense against viral infection and cancer. By combining biochemical experiments with sequencing technologies, she aims to map modified RNA molecules and determine how these chemical marks alter immune signaling. At The Rockefeller University, Hope Funds for Cancer Research Fellow Jaejin Kim, PhD, will investigate how tissues retain molecular memories of inflammation. Conditions such as eczema, psoriasis, and inflammatory bowel disease can recur in the same anatomical locations, suggesting that stem cells preserve information about previous injury. Kim, working with Elaine Fuchs, PhD, will identify the genes and mechanisms that encode these memories and distinguish beneficial regenerative responses from persistent programs that increase cancer risk.

Metabolism is another central theme among the new fellowships. At The J. David Gladstone Institutes, Connie and Bob Lurie Fellow Rachael A. McMinimy, PhD, will study the pyruvate dehydrogenase complex, an enzymatic switch that determines whether glucose-derived carbon enters mitochondrial respiration. Normal cells often use mitochondria to generate energy efficiently, while many cancer cells redirect glucose through alternative pathways that support rapid proliferation and the production of cellular building blocks. McMinimy is investigating a newly identified mechanism that regulates the pyruvate dehydrogenase complex through selective protein degradation. Manipulating this pathway could force tumor cells to rely more heavily on mitochondrial metabolism and reduce their ability to grow. At Stanford, Robertson Foundation Fellow Gayathri Muthukumar, PhD, will examine post-translational modifications on cell-surface and intracellular membrane proteins. Tumor cells often carry unusually dense coatings of sugar molecules, known as glycans, which may alter signaling and help cancers avoid immune attack. Muthukumar will combine molecular mapping with precision genetic screens to determine which modifications promote oncogenesis. The findings could yield new therapeutic targets and diagnostic markers.

At the Massachusetts Institute of Technology, Timmerman Traverse Fellow Angelos Pistofidis, PhD, will investigate transcription termination factor 2, or TTF2, a protein involved in the mechanics of cell division. During mitosis, duplicated chromosomes must be compacted and accurately separated so that each daughter cell receives a complete genome. Alterations in TTF2 have been linked to defective chromosome segregation, DNA damage, and cell death, and many cancers appear to depend on the protein for survival. Pistofidis will use structural biology, biochemistry, and single-molecule biophysics to determine how TTF2 functions at the molecular level and identify weaknesses that could be exploited by future drugs. At Columbia University, National Mah Jongg League Fellow Christina A. Stephens, PhD, will study adhesion G protein-coupled receptors, or aGPCRs, a class of surface proteins increasingly associated with cancer. These receptors can influence cell growth and communication, but their activation mechanisms remain obscure. Using single-molecule microscopy and molecular dynamics simulations, Stephens will define how aGPCRs switch between inactive and active states and use that information to optimize therapeutic strategies against tumors carrying these receptors.

Two Fellows will investigate problems at the intersection of cancer and infectious disease. At The Rockefeller University, Timmerman Traverse Fellow Bailey Schultz, PhD, will study the growth and division of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis. Approximately one-quarter of the global population is estimated to have been infected with M. tuberculosis, and the disease kills more people than any other pathogen. Tuberculosis and cancer intensify one another: previous infection is associated with increased risk of some cancers, while tumors and chemotherapy can weaken immunity and make infection more dangerous. Some cancer immunotherapies may also reactivate dormant tuberculosis. Schultz will use genome-wide CRISPR-based approaches to identify bacterial genes that control cell growth and division, pointing to potential drug targets while anticipating genetic routes to antibiotic resistance. At Weill Medical College of Cornell University, Robertson Foundation Fellow Yang Su, PhD, will focus on c-MYC, a master regulator of cancer growth that has long been considered difficult to drug directly. Su will investigate a newly described form of chemical modification in c-MYC messenger RNA involving the addition of two methyl groups. Determining which enzyme installs the modification and how it changes c-MYC stability or activity could expose a new strategy for suppressing tumors driven by this oncogene.

The final project addresses the evolution of cancer within individual tumors. At Dana-Farber Cancer Institute, Robertson Foundation Fellow Shuya Wang, PhD, will work with David S. Pellman, MD, to understand how genome instability creates epigenetic diversity. Cancer cells in the same tumor can activate different genes, enabling some subpopulations to survive treatment, adapt to changing conditions, or become more aggressive. Wang will identify the genes and pathways that connect genomic instability with changes in the epigenome, the regulatory layer that controls gene activity without altering the underlying DNA sequence. Understanding how this heterogeneity arises could reveal ways to slow tumor evolution and treatment resistance. “There’s so much talent and excitement and passion and energy at this stage of a scientist’s career,” said current Damon Runyon-Timmerman Traverse Fellow Antonio J. LaPorte, PhD, emphasizing the importance of independent support for young investigators. Yung S. Lie, PhD, President and CEO of Damon Runyon, said the Foundation remains committed to backing researchers whose discoveries in prevention, diagnostics, and therapeutics might otherwise go unfunded. Since its founding in 1946, Damon Runyon says it has invested more than $491 million in nearly 4,100 scientists, including 13 researchers who later received Nobel Prizes.

Web References: http://damonrunyon.org/

Keywords: Damon Runyon Cancer Research Foundation, cancer research, postdoctoral fellows, cancer biology, cancer immunotherapy, gene regulation, epigenetics, cancer metabolism, tuberculosis, molecular therapeutics, CARM1, c-MYC, TTF2, cryptic antigens, RNA modification

At the heart of this discovery lies RNA Polymerase I (Pol I), the enzyme responsible for transcribing ribosomal RNA genes—a vital step in the assembly of ribosomes, the cellular machinery that translates genetic codes into functional proteins. While aberrant ribosome biogenesis has historically been recognized as a hallmark of cancer, this study elucidates a previously unappreciated layer of complexity: the connection between rRNA synthesis and the regulation of RNA splicing, a process that enables a single gene to produce diverse protein variants through selective editing of precursor RNA transcripts.

Led by Dr. Marikki Laiho, an expert in Radiation Oncology and Molecular Radiation Sciences, the team demonstrated that pharmacological inhibition of Pol I instigates a unique cellular stress response that reprograms RNA splicing patterns in cancer cells. This reprogramming selectively impairs tumor growth by altering the production of protein isoforms crucial for cancer cell survival and proliferation. Central to this mechanism are ribosomal proteins RPL22 and its paralog RPL22L1, as well as the MDM4 protein, all of which participate in coordinating the dynamic crosstalk between ribosome biogenesis and splicing modulation.

The study employed BMH-21, a small molecule developed in collaboration with Johns Hopkins pharmacology specialists, to obstruct Pol I activity in a comprehensive panel of over 300 cancer cell lines. Strikingly, cancers harboring mutations in RPL22 or exhibiting elevated levels of RPL22L1 and MDM4 were particularly vulnerable to Pol I inhibition. Notably, these molecular alterations frequently occur in tumors characterized by mismatch repair deficiency (MMRd), a genetic condition involving defects in DNA repair pathways. MMRd leads to an accumulation of genomic mutations and is commonly observed in colorectal, gastric, and uterine cancers, which often show resistance to standard therapies.

Further extending their findings beyond cell culture, the researchers evaluated a novel Pol I inhibitor, BOB-42, in animal tumor models that recapitulate patient-derived malignancies bearing these critical genetic signatures. Treatment with BOB-42 resulted in significant tumor suppression, with reductions in tumor size reaching up to 77% in aggressive melanoma and colorectal cancer models. These preclinical successes highlight the therapeutic potential of targeting the rRNA synthesis-splicing axis in cancers that evade existing treatment modalities.

Beyond its tumor-suppressive effects, the study suggests a compelling link between altered splicing patterns induced by Pol I inhibition and enhanced tumor immunogenicity. By reshaping the protein landscape presented by cancer cells, changes in RNA splicing may unmask novel tumor antigens, potentially improving recognition by the immune system. Consequently, the combination of Pol I inhibitors with immunotherapy agents could synergize to overcome immune evasion, a major hurdle in effective cancer treatment.

Dr. Laiho elaborated on this innovative concept, emphasizing the dual role of the ribosomal protein RPL22. Traditionally viewed as a structural ribosomal component, RPL22 also exerts regulatory control over selective RNA splicing. This dual functionality underscores a deeper level of cellular regulation wherein rRNA synthesis and splicing are intimately coordinated to dictate cancer cell behavior. Such a paradigm shift in understanding ribosome-related oncogenic processes could lead to transformative advances in precision oncology.

The implications of this work extend beyond therapeutic targeting of Pol I. By delineating the molecular underpinnings of cancer cells’ sensitivity to rRNA synthesis inhibition, the study offers insights into the vulnerabilities of mismatch repair-deficient tumors, which are often characterized by high mutation burden and poor prognosis. Therapeutic strategies that exploit these vulnerabilities could fill an urgent need for more effective treatments in this patient population.

Moreover, the discovery paves the way for future investigations into the role of ribosomal proteins in RNA metabolism and how their dysregulation contributes to tumorigenesis. The intersection of ribosome biogenesis with RNA splicing regulation represents a fertile frontier for molecular oncology research, promising new biomarkers and drug targets for a variety of cancers.

This pioneering research involved a multidisciplinary team, including insights from experts in cancer biology, pharmacology, and radiation oncology. Their collaborative efforts, complemented by funding from prominent institutions such as the National Institutes of Health and private foundations, exemplify the concerted push toward unraveling complex cancer vulnerabilities.

Acknowledging the translational potential of their findings, the researchers hold intellectual property rights related to Pol I inhibitors, underscoring the practical ambitions of bringing these discoveries from bench to bedside. Future clinical trials assessing the safety and efficacy of compounds like BMH-21 and BOB-42 will be critical to validate their therapeutic promise in cancer patients.

The study profoundly redefines our understanding of how ribosomal RNA synthesis intricately controls tumor cell physiology, revealing an exploitable Achilles’ heel within cancer’s machinery. By co-opting fundamental processes of RNA production and splicing regulation, this research charts a novel course for developing targeted, mechanism-based cancer therapies that could markedly improve patient outcomes in malignancies refractory to current interventions.

Subject of Research: Cancer Biology, Ribosome Biogenesis, RNA Splicing, Therapeutic Targeting
Article Title: Ribosomal RNA Synthesis and RNA Splicing Interplay as a Novel Tumor-Suppressive Pathway in Mismatch Repair-Deficient Cancers
News Publication Date: June 18, 2024
Web References:

• Johns Hopkins Kimmel Cancer Center: https://www.hopkinsmedicine.org/kimmel-cancer-center
• Department of Radiation Oncology and Molecular Radiation Sciences: https://www.hopkinsmedicine.org/radiation-oncology
• Cell Chemical Biology Journal: https://www.cell.com/cell-chemical-biology/home
  Image Credits: Courtesy of Cell Chemical Biology
  Keywords: Cells, Cancer Stem Cells, Ribosomal RNA, RNA Polymerase I, Mismatch Repair Deficiency, RPL22, RNA Splicing, Tumor Suppression, Immunotherapy, Cancer Therapeutics

Cellular identity is typically established during embryonic development, during which cells, such as nerve cells and liver cells, differentiate and are determined to fulfill specific roles. Post-differentiation, these cells usually adhere to their predetermined paths. However, the dynamics change dramatically in the context of cancer, where tumor cells exhibit a remarkable ability to revert to more primitive states, essentially reactivating embryonic programs that allow them to alter their identity. This phenomenon, often referred to as cellular plasticity, poses significant challenges in the context of tumor progression and metastasis.

The reprogramming capability of cancer cells enables them to detach from their originating tissue, migrate throughout the body, and then re-establish themselves in distant organs, where they can form new tumors. Such plasticity not only facilitates metastasis but also complicates treatment strategies, as these cells can evade therapies designed to target their original phenotypes. The key question motivating researchers, including molecular biologist Moritz Mall from DKFZ, is how to effectively curb the plasticity of these malignant cells to prevent tumor formation and dissemination.

To understand cellular identity regulation more deeply, Mall and his team explore the mechanisms by which highly specialized cell types are generated from a common genetic blueprint. While genes encode the potential for various cell types, a sophisticated regulatory network governs their expression, ensuring that only specific genes are active depending on the cell’s identity. This intricate regulation is likened to the philosophical concepts of Yin and Yang, emphasizing the delicate balance of forces at play that influence whether genes are turned on or silenced.

While master regulators that promote phenotype changes in cells have been well studied, much less attention has gone to the antagonistic factors— the guardians that prevent undesired transformations in cells. Seeking to uncover such molecules, Mall collaborated with Judith Zaugg from EMBL, leveraging computational tools to identify gene switches that might function as guardians. This innovative approach involved computationally profiling thousands of gene switches against extensive databases of existing research, leading to the identification of about 30 potential guardian candidates worthy of further investigation.

Among these candidates, PROX1 emerged as particularly promising. The research team delved into its function using a liver cancer model, discovering that PROX1 plays a critical role in preserving hepatocyte identity. In experiments where PROX1 was knocked down, liver cells began to lose their specialized characteristics, emphasizing the molecule’s influence. Furthermore, augmenting PROX1 activity inhibited the versatility of cancer cells, demonstrating the molecule’s potential to counteract the effects of potent cancer mutations, specifically in genes like p53 and Myc. This sets a precedent for viewing PROX1 as a pivotal guardian against tumorigenesis.

Interestingly, PROX1 must maintain a constant state of activity to fulfill its protective role in liver cells, diverging from many other gene switches that operate on a more transient basis. This constant activation is a crucial factor that underscores the complexity of cellular regulation and the mechanisms that underpin identity preservation versus plasticity in liver cells. Ongoing research aims to highlight how sustained activity of guardians like PROX1 could be leveraged as a therapeutic strategy to combat liver cancer by enhancing their function locally within the organ.

As the field continues to evolve, the discovery of PROX1 as a guardian molecule heralds a new frontier in cancer therapy. Increasing its activity locally in liver tissues could mark a novel preventative measure or treatment option for liver cancer. It remains uncertain whether other organs harbor similar guardian molecules, but the potential for broader applications, alongside the insights gained about cellular plasticity, paves the way for future research endeavors.

The collaboration between DKFZ, HITBR, and EMBL demonstrates the synergy of interdisciplinary research in addressing complex biological questions. By focusing on the interplay of different cellular forces and their role in cancer biology, researchers are poised to unlock new paradigms in cancer treatment. As they delve deeper into the nuances of gene regulation and cell identity, the potential implications for human health and personalized medicine are vast, hinting at transformative advancements in our understanding and management of cancer.

In summary, the landmark discovery of PROX1 reinforces the importance of investigating the regulatory landscapes that govern cell identity, particularly in the context of oncology. With further research and exploration, the insights derived from such guardian molecules hold promise for not only enhancing our understanding of tumor biology but also improving therapeutic strategies aimed at mitigating the impact of cancer.

Subject of Research: The role of PROX1 as a guardian molecule in maintaining liver cell identity and its implications in cancer progression.

Article Title: A Guardian Molecule in the Fight Against Liver Cancer

News Publication Date: 2025

Web References: Nature Genetics DOI: 10.1038/s41588-025-02081-w

References: Lim B et al: Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumourigenesis. Nature Genetics, 2025.

Image Credits: Not specified.

Keywords: Cancer research, liver cancer, PROX1, cellular identity, cellular plasticity, tumorigenesis, gene regulation, biomedical research.