Researchers report that treatment resistance in advanced prostate cancer is driven by epigenetic lineage plasticity rather than genetic mutations, raising new possibilities for combination therapies and biomarker development in clinical laboratories.
Scientists at the Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University have identified a molecular mechanism that helps explain why advanced prostate cancers often become resistant to modern hormone-based therapies—and, importantly, how that resistance may be reversed. The findings, published in Nature, describe how prostate tumor cells evade treatment through epigenetic reprogramming rather than genetic mutation, and present preclinical evidence for a drug strategy that could restore treatment sensitivity.
For clinical laboratory professionals, the study highlights the growing relevance of epigenetic regulation, lineage plasticity, and biomarker-driven therapeutic strategies in oncology.
From Hormone Therapy to Lineage Switching
Over the past decade, androgen receptor (AR) inhibitors have become the standard of care for advanced prostate cancer. While initially effective, these therapies frequently drive tumors to adopt a neuroendocrine-like state, a highly aggressive phenotype that no longer depends on androgen signaling and is largely resistant to existing drugs. This transition has posed a longstanding puzzle for cancer biologists and clinicians alike, as it occurs without obvious DNA mutations.
The research builds on decades of work by Michael Shen, PhD, co-leader of the tumor biology and microenvironment program at HICCC, who studies “lineage plasticity”—the ability of cancer cells to change identity under therapeutic pressure. Prior work from Shen’s lab showed that this lineage shift is driven by epigenetic changes rather than permanent genetic alterations, pointing to reversible factors.
To identify the epigenetic drivers, Shen partnered with other Columbia researchers. The team homed in on NSD2, a gene that regulates cellular processes but can also cause cancers during abnormal activity. (Photo credit: Columbia University)
Targeting an “Undruggable” Enzyme to Restore Drug Sensitivity
NSD2 had long been considered “undruggable,” complicating efforts to translate the discovery into a therapeutic strategy. However, recent advances in small-molecule inhibitor development changed that outlook. Using a newly developed NSD2 inhibitor, the researchers demonstrated in prostate cancer models that blocking NSD2 caused neuroendocrine tumors to lose their resistance to therapies.
While NSD2 inhibition alone did not kill tumor cells, its impact was dramatic when combined with other inhibitors. The combination therapy restored sensitivity to standard hormone treatments, effectively resensitizing previously resistant cancers.
For the clinical laboratory community, these findings underscore the importance of epigenetic markers in cancer diagnostics. The ability to distinguish lineage states—and potentially monitor transitions between them—could influence future testing strategies, companion diagnostics, and treatment selection.
More broadly, the study provides one of the clearest demonstrations to date that epigenetically driven treatment resistance can be reversed. Because lineage plasticity is common across multiple tumor types, including small cell lung cancer, the NSD2 pathway may represent a broader therapeutic and diagnostic target.
As these findings move toward clinical testing, laboratories may play a central role in translating epigenetic insights into actionable oncology care.
Researchers have identified thousands of protein-free, circular RNA molecules living inside human-associated bacteria, raising new questions for microbiology labs about how life is classified.
Laboratory leaders accustomed to classifying organisms as bacteria, viruses, or parasites may soon need to account for something entirely different. Researchers have identified a previously unknown class of RNA molecules living inside bacteria associated with the human body—entities that replicate but do not fit into any existing biological category.
The structures, called “obelisks,” are circular RNA molecules found primarily in bacteria from the human mouth and gut. They are neither living cells nor conventional viruses. Instead, they exist as short loops of RNA that replicate within microbial hosts through mechanisms that scientists do not yet understand.
Protein-Free RNA Replicators Emerge from Large-Scale Metagenomic Analysis
What makes obelisks particularly unusual is what they lack. According to the researchers, the RNA loops are “protein-free, RNA-only replicators.” They do not encode proteins, nor do they form protective capsids or membranes. This places them outside established definitions of viruses, plasmids, or other mobile genetic elements.
The discovery emerged from a large-scale analysis of publicly available metagenomic data drawn from human-associated microbial communities. Using computational tools designed to identify circular RNA structures, the research team screened vast genomic libraries from oral and intestinal microbiomes.
That effort revealed more than 3,000 distinct obelisk sequences, many of which appeared repeatedly across samples from different individuals and geographic regions. The work was led by Nobel laureate Andrew Fire of Stanford University and published as a preprint on bioRxiv.
To ensure the findings were not artefacts of sequencing or data processing, the team applied stringent filtering criteria. After removing false positives, they identified conserved genetic motifs shared among multiple obelisks. Many of the RNA loops were found embedded within bacterial genomes, suggesting they replicate inside microbial cells and may have adapted to specific bacterial hosts over time.
Unknown Function, Broad Implications for Microbiology and Evolution
Although obelisks resemble plant viroids, non-coding, circular RNAs that infect plants, the researchers note a key difference: obelisks have so far been identified only in bacteria associated with humans. Their biological role remains unknown.
At present, there is no evidence linking obelisks to disease. However, their presence in bacteria that support digestion, immune function, and other critical processes raises questions about whether they may have indirect effects on human health. Researchers also observed that different obelisk variants appear in specific body sites, hinting at localized adaptation within the microbiome.
Beyond immediate clinical relevance, the discovery has broader implications for microbial classification and evolutionary biology. Obelisks do not conform to known categories, challenging long-standing assumptions about what constitutes a replicating biological entity.
Some scientists suggest these RNA structures could inform theories about early life on Earth, when self-replicating RNA may have existed before cells and proteins. As one review in Royal Society Open Science notes, such entities sit at the edge of life as currently defined.
For laboratory leaders, the finding highlights the expanding reach of metagenomic sequencing and bioinformatics. As clinical and research labs generate and analyze ever-larger datasets, they are increasingly likely to encounter biological signals that defy traditional taxonomy.
Whether obelisks prove to be ancient evolutionary relics or modern molecular passengers, their discovery is a reminder that the microbiome—and the lab tools used to study it—still holds fundamental surprises.
Investigators identified more than 100 proteins linked to inherited cancer risk and dozens of existing drugs that could be repurposed for cancer prevention.
Researchers at Vanderbilt University Medical Center (VUMC) and the University of Calgary have developed a new analytical framework that integrates genomic, proteomic, and electronic health record (EHR) data to uncover proteins linked to cancer risk and to identify existing drugs that may be repurposed for cancer prevention. The approach, described in a study published Dec. 2 in the American Journal of Human Genetics, represents a step toward translating large-scale genetic discoveries into actionable prevention strategies across multiple cancer types.
For clinical laboratory directors, the new framework offers a glimpse of how combined genomic, proteomic, and EHR datasets could soon reshape biomarker discovery and test development.
Genome-wide association studies (GWAS) have already identified hundreds of genetic variants associated with increased cancer risk, particularly for breast, colorectal, and prostate cancers, as well as dozens of variants linked to lung, pancreatic, and ovarian cancers.
However, most of these studies have focused on genetic variation and gene expression rather than the downstream proteins that ultimately drive biological function and are more directly targetable by drugs.
Xingyi Guo, PhD, associate professor of medicine in the Division of Epidemiology at VUMC and a co–senior author of the study said, “Previous research, including our work, has identified hundreds of putative cancer susceptibility genes that could be regulated by these risk variants; however, most dysregulated gene expression has not been thoroughly investigated at the protein level.” (Photo credit: VUMC)
Integrating GWAS and Proteomics to Identify Druggable Cancer Risk Proteins
To bridge that gap, the investigators combined large GWAS datasets for six major cancers—breast, colorectal, lung, ovarian, pancreatic, and prostate—with population-scale proteomics data drawn from more than 75,000 participants. The data came from multiple large cohorts, including the Atherosclerosis Risk in Communities (ARIC) study, deCODE genetics, and the UK Biobank Pharma Proteomics Project. The goal was to identify proteins whose circulating levels are associated with inherited cancer risk.
“To deepen the understanding of causal mechanisms and enhance drug discovery efforts, it is imperative to explore data from transcriptomic to proteomic studies,” said Zhijun Yin, PhD, MS, associate professor of biomedical informatics at VUMC and co–senior author, along with Quan Long, PhD, associate professor of biochemistry and molecular biology at the University of Calgary.
Using this integrated approach, the research team identified 365 proteins associated with cancer risk across the six cancer types studied. Through additional analyses to prioritize the most robust findings, they narrowed this list to 101 risk proteins. Notably, 74 of these proteins had not been previously reported as being linked to cancer susceptibility, highlighting the potential of proteomics to reveal novel biology that may be missed by gene-level analyses alone.
The researchers then evaluated whether these risk proteins could be therapeutically targeted. By systematically annotating the proteins using multiple pharmaceutical and drug-development databases, they assessed whether any were already the targets of approved drugs or agents in clinical testing. This step was designed to identify opportunities for drug repurposing—using existing medications for new preventive indications.
“Traditional drug discovery faces challenges of escalating costs, lengthy timelines, and high failure rates. Drug repurposing is a promising strategy to identify new applications for existing drugs with well-documented characteristics,” Guo said.
Among the 101 prioritized proteins, the investigators identified 36 that were considered druggable and potentially targetable by 404 drugs that are already approved or undergoing clinical trials. Of these, 19 proteins were targeted by drugs currently approved or in development for cancer treatment, suggesting a possible extension of oncology therapeutics into the prevention setting.
EHR-Based Analyses Suggest Reduced Cancer Risk with Certain Approved Drugs
To explore real-world relevance, the team leveraged more than 3.5 million de-identified EHRs from VUMC. Using this data, they conducted simulated clinical trials to examine associations between drug exposure and cancer risk. Several approved medications showed signals consistent with reduced cancer risk. One example highlighted in the study was acetazolamide, a diuretic, which was associated with a reduced risk of colorectal cancer in the EHR-based analyses.
“Our findings offer additional insights into therapeutic drugs targeting risk proteins for cancer prevention and intervention,” Yin said. “It is essential to evaluate the effects of the reported candidate drugs through both in vitro and in vivo assays in future research.”
EHRs are rich in diagnostic data, so there is a clear connection between the researchers’ drug discovery efforts and the information that clinical laboratory test results can provide.
Teen researchers in suburban Atlanta may have cracked one of diagnostics’ toughest challenges: early Lyme detection. Their CRISPR test shows promise for identifying infection long before standard tools can.
For laboratory leaders navigating a rapidly shifting diagnostics landscape, a new signal of future innovation is emerging from an unexpected place: a suburban high school lab in Georgia. Lambert High School’s student researchers have engineered a CRISPR-based prototype that may detect Lyme disease days after infection—a potential breakthrough that, if validated, underscores how quickly synthetic biology is advancing and how early the next generation is entering the field.
Clinical laboratory professionals will be happy to note the promising work that the next generation of lab scientists has started.
The students, all part of Lambert High School’s elite synthetic biology team near Atlanta, set out to solve what senior Claire Lee called one of medicine’s most stubborn blind spots. “We’re doing something in our high school lab that could potentially have a huge impact for, like, millions of people,” she said. “This thing could help save lives.”
Using CRISPR, the powerful gene-editing tool, the teens developed a prototype test that appears capable of detecting Lyme disease just two days after infection, far earlier than the two-week window required by current assays. Although based on simulated blood serum and still in proof-of-concept stages, their findings were compelling enough to earn praise from scientists and secure a top-10 finish at the International Genetically Engineered Machine (iGEM) competition in Paris.
High School Genetic Engineers With an Ambitious Plan
Led by team captains Sean Lee and Avani Karthik, the CRISPR-based system targets a protein produced in the earliest moments of Lyme infection. “One of the biggest problems with Lyme is the lack of, like, being able to diagnose it,” Karthik said. They even met one patient who went “15 years without a diagnosis.”
Their idea was to use CRISPR to cut away extraneous DNA, revealing the protein so it could be detected with a rapid, kit-style test which is much like the COVID-19 diagnostic format. The students also explored using a different CRISPR system to block Lyme-causing bacteria as a potential therapeutic alternative to antibiotics.
But the team’s vision initially met resistance. Biotechnology teacher Kate Sharer said she warned students, “This project in particular, I told them: this is very high risk, high reward.” She admitted, “I couldn’t imagine any of this working,” though she supported their efforts. External experts were similarly cautious. As co-captain Sean Lee recalled,
“They did tell us in the beginning that this might not be so feasible because you’re trying to tackle such a big thing.”
A Top-Notch Lab Inside a Public School
Lambert’s program stands out nationally. Its county-funded, corporate-supported lab rivals those at universities, and the school draws families who relocate specifically for opportunities like iGEM. The team—entirely Asian-American this year and mostly children of immigrants—accepts roughly 10 members from about 100 applicants. Students pitch project ideas, test into the program, and endure what the team calls “insanely long hours.”
In September, after months of work, the students saw the data they had hoped for. Their system flagged early Lyme markers in as little as two days. It wasn’t human-blood–validated, but it was enough to push the project forward.
They spent the last weeks before the competition building a website, compiling results and pulling all-nighters to finalize their presentation.
Showdown in Paris
Arriving in Paris in late October, Lambert joined more than 400 teams from around the globe. Projects ranged from designing Mars-ready crops to developing enzymes to fight indoor mold. Janet Standeven, who oversees iGEM’s high school division and founded Lambert’s program, said she believes synthetic biology education is essential.
Janet Standeven noted that when federal funding for statewide programs was cut, she felt “absolutely devastated” and “angry,” though a judge has since temporarily restored the support. (Photo credit: Engineering Biology Research Consortium)
Stanford professor and iGEM co-founder Drew Endy warned that the U.S. risks losing ground in biotechnology as China accelerates national investment. “It’s urgent that leadership of the next generation of biotechnology has a strong presence in America,” he said. After seeing Lambert’s work, he added, “They appear to have developed a better diagnostic for Lyme disease than anything I’ve seen before.”
China’s Great Bay team ultimately won the grand prize. Lambert, nominated in five categories, earned the award for best software tool and finished among the top 10 high school teams worldwide—the only American team to do so.
For the Lambert students, the recognition mattered, but the mission mattered more. As Claire Lee put it, working on a test with the potential to save lives made every long night “worth it.”
Researchers in Singapore unveil a breakthrough RNA strategy that simultaneously silences KRAS mutations and activates immune defenses in hard-to-treat tumors.
As precision oncology moves deeper into RNA-based and immune-modulating therapies, clinical laboratories are finding themselves at the center of a rapidly evolving frontier. New research from Singapore signals just how quickly that future is arriving. In two complementary studies, scientists at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), unveiled a dual-action RNA strategy that targets KRAS—one of cancer’s most stubborn and historically “undruggable” genes—while simultaneously jump-starting the immune system to recognize and attack tumors.
For lab leaders, the findings hint at a coming era in which molecular diagnostics, immune-response markers, and vesicle-based delivery technologies converge in routine care.
Researchers from NUS Medicine, together with collaborators from Nanyang Technological University (NTU), A*STAR, and international partners, focused on KRAS because of its prevalence and difficulty to treat. KRAS mutations lock the gene’s molecular switch in a permanent “on” state, driving constant cell growth and helping tumors hide from immune detection. These mutations appear in more than 90% of pancreatic cancers and are also common in lung and colorectal malignancies. Traditional drug approaches have faltered because the KRAS protein binds its signaling molecules too tightly and lacks accessible pockets for small-molecule inhibitors.
A Dual RNA Strategy to Break KRAS Resistance
To get around these challenges, the team paired two RNA tools: antisense oligonucleotides (ASOs) to silence mutant KRAS and an immunomodulatory RNA (immRNA) to activate RIG-I, an innate immune pathway usually triggered by viral infections. Turning on RIG-I sends an antiviral-like alarm through the cell, prompting immune activation that can help unmask tumor cells. Both RNA agents were delivered using red blood cell–derived extracellular vesicles (RBCEVs), natural carriers that can transport nucleic acid drugs safely and efficiently into tumor tissue.
The first study, published in Theranostics, demonstrated that this ASO–immRNA combination effectively killed KRAS-driven cancer cells in lung, colorectal, and pancreatic models. The therapy blocked oncogenic KRAS activity while converting “cold” tumors—those typically invisible to immune attack—into “hot” tumors that attract immune cells. In laboratory models, the approach reduced tumor burden, improved survival, and spared healthy cells.
Preclinical Progress in Pancreatic Cancer
The second study, appearing in the Journal of Controlled Release, advanced the platform for pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the deadliest human cancers, with a five-year survival rate around 10%. It often spreads throughout the peritoneal cavity, leaving patients with few effective treatment options.
In preclinical models of PDAC with peritoneal metastasis, the dual-RNA therapy markedly suppressed tumor growth, restricted abdominal spread, and extended survival. Importantly, safety testing showed no observable toxicity. Investigators say this strengthens the case for eventual clinical trials and highlights the broader versatility of extracellular vesicles as delivery vehicles across multiple RNA-based modalities.
Associate professor Minh Le, Department of Pharmacology, and Institute for Digital Medicine (WisDM), NUS Medicine noted, “Our EV platform precisely targets mutants, sparing healthy tissue, and synergizes KRAS knockdown with RIG-I activation to unleash interferons, immunogenic cell death, and T-cell memory—halting tumor growth and extending survival without toxicity.” (Photo credit: NUS)
For clinical laboratories, these advances signal more than a scientific milestone—they point to a near future in which labs may need to measure KRAS knockdown, track immune-activation signatures, quantify extracellular vesicle uptake, and support increasingly complex molecular workflows. While the therapy remains in the preclinical phase, the implications are clear: RNA-based therapeutics and EV-mediated delivery are moving quickly toward clinical reality, and laboratories will play a central role in bringing those innovations to patients.
This article was created with the assistance of Generative AI and has undergone editorial review before publishing.
The CAP- and CLIA-validated microRNA-371a-3P assay promises earlier detection, fewer CT scans, and more precise treatment decisions for a high-risk patient population.
According to a press release, UC San Diego Health has become the first health system in the United States to offer a clinically validated blood test for testicular cancer. This advance could potentially redefine diagnostic workflows, reduce reliance on imaging, and sharpen treatment decisions for a patient population that often faces both overtreatment and missed recurrences.
The assay, more than a decade in development, measures microRNA-371a-3P, a biomarker shown to detect the presence of testicular cancer cells with about 90% accuracy. Until now, clinicians and clinical laboratories have had limited tools to determine which patients require surgery, chemotherapy, or simply surveillance, especially when imaging is inconclusive.
Testicular cancer strikes roughly 10,000 people annually, primarily men between 18 and 45, yet existing serum markers fail to capture the majority of cases. As a result, laboratories and oncologists have historically struggled with staging uncertainty, unnecessary chemotherapy, and delayed recognition of recurrence. About one-third of patients experience relapses after orchiectomy despite normal CT imaging.
The press release explained that the biomarker’s sensitivity and specificity offer a clearer, earlier signal of active cancer biology—information that can materially change treatment plans.
Further, the test can be used across the care continuum. Before surgery, it can help confirm whether an abnormal testis is malignant and guide surgical decision-making. Post-operatively, it can help determine which patients truly need systemic therapy or further intervention. During surveillance, it may detect recurrence earlier than imaging, allowing less intensive and more precisely timed treatment.
For laboratories, one of the most consequential implications is the potential to reduce the reliance on repeated CT scans, as they carry radiation exposure, cost burdens, and logistical challenges. A validated blood-based alternative, if adopted more widely, could shift surveillance algorithms across health systems.
A Model for Translational Collaboration
The test is currently available for patients at UC San Diego Health and will open to external referrals later this year, allowing outside clinicians and pathology departments to submit samples. It is fully CAP-accredited and CLIA-certified, positioning it for broader adoption by cancer centers seeking higher-resolution molecular insight without expanding imaging capacity.
“This breakthrough represents the kind of investment in innovation that can save lives while improving quality of life for cancer survivors,” said Diane Simeone, MD, director of the Moores Cancer Center at UC San Diego Health. (Photo credit: UC San Diego Health)
For the urology and oncology teams, the test represents years of translational research. For laboratories, it represents a milestone in bringing microRNA-based diagnostics into routine clinical use.
Integrating Results into Multidisciplinary Care
Each test result will feed into UC San Diego Health’s molecular tumor board, a multidisciplinary group that meets every two weeks to review every patient case and interpret biomarker findings in the context of clinical, imaging, and pathological data. For laboratory professionals, this embedded oversight ensures that results are used appropriately and helps refine test performance insights over time.
For labs nationwide, the launch signals a turning point: a real-world, regulated microRNA test with immediate clinical impact—and a template for how laboratory medicine can lead in closing long-standing diagnostic gaps.
This article was created with the assistance of Generative AI and has undergone editorial review before publishing.
