eLife: latest articles by subject

Tumors mimic the niche to inhibit neighboring stem cell differentiation

swzhao@nankai.edu.cn (Chang Sun) — Fri, 15 May 2026 00:00:00 +0000

Although it is well established that stem cells maintain tissue homeostasis while tumors disrupt it, the mechanisms by which tumors influence the development of nearby stem cells remain poorly understood. Using Drosophila ovaries as a model system, here we discovered that bam or bgcn mutant germline tumors inhibit the differentiation of neighboring wild-type germline stem cells (GSCs). Mechanistically, these tumor cells mimic the stem cell niche by secreting the bone morphogenetic protein (BMP) ligands Dpp and Gbb, but at reduced levels, resulting in moderate BMP signaling activation in adjacent GSCs. Such BMP signaling activation is sufficient to repress bam transcription, thereby blocking GSC differentiation. To our knowledge, this is the first example that tumors can functionally mimic a stem cell niche to inhibit the differentiation of neighboring wild-type stem cells. Similar regulatory paradigms may operate in mammalian tissues, including humans, during tumorigenesis.

HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content

sfrangos@uoguelph.ca (Cezar M Khursigara) — Wed, 06 May 2026 00:00:00 +0000

It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I–IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

david.papadopoli@mail.mcgill.ca (Daina Avizonis) — Tue, 05 May 2026 00:00:00 +0000

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.

RadD from Fusobacterium nucleatum engages NKp46 to promote antitumor cytotoxicity

oferm@ekmd.huji.ac.il (Ahmed Rishiq) — Fri, 01 May 2026 00:00:00 +0000

Fusobacterium nucleatum, a gram-negative bacterium implicated in periodontal disease, contributes to tumor progression in various cancers. Whether the presence of F. nucleatum inhibits tumor progression of some cancers is largely unknown. Here, we identify an interaction between F. nucleatum and the natural killer (NK) cell receptor NKp46. Analysis of TCGA datasets revealed that the co-occurrence of F. nucleatum and high NKp46 expression correlates with improved survival in head and neck cancers but not in colorectal cancers. Using binding assays, we demonstrate that both human NKp46 and its murine ortholog, Ncr1, directly recognize the fusobacterial adhesin RadD. Genetic deletion of radD or blockade of NKp46 significantly impaired NK cell-mediated cytotoxicity in vitro and promoted tumor-cell growth. In vivo, infection with F. nucleatum accelerated tumor progression, with an exacerbated effect observed in the absence of RadD or NKp46. These findings highlight RadD as a critical ligand for NKp46 and establish the NKp46–RadD axis as a key interface in host–microbe–tumor interactions, offering a novel target for immunotherapeutic intervention in cancer influenced by microbial factors.

PTEN restrains SHH medulloblastoma growth through cell autonomous and nonautonomous mechanisms

joynera@mskcc.org (Alexandra L Joyner) — Fri, 17 Apr 2026 00:00:00 +0000

A third of patients with the pediatric cerebellar tumor Medulloblastoma (MB) have mutations that activate Sonic hedgehog (SHH) signaling (SHH-MB subgroup). The contribution of secondary mutations to tumor severity, however, is not clear. PTEN mutations are enriched in the SHH-1 subtype that has the lowest survival rate. Widespread heterozygous loss of Pten in two SHH-MB mouse models increases penetrance and accelerates onset of differentiated tumors. We delineated cellular and transcriptional changes that accelerate tumor growth and cause differentiation using a sporadic SHH-MB mouse model expressing oncogenic SmoM2 in rare cerebellar granule cell precursors (GCPs) and scRNA-seq analysis. Homozygous but not heterozygous sporadic loss of Pten resulted in rapid acceleration of tumor growth and end-stage disease by 40 days, compared to ~25% survival in control SmoM2 mice at 100 days. Heterozygous PTEN mutations, therefore, should negatively impact disease outcome primarily with germline mutations. Loss of Pten in normal or SmoM2-expressing GCPs increased proliferation and enhanced progenitor state initially, but by 12 days Pten mutant SmoM2 tumors were highly differentiated due to increased survival of non-proliferating GCPs. Furthermore, macrophage infiltration and cytotoxicity appeared reduced in differentiated regions of tumors lacking Pten, indicating cell nonautonomous changes could also contribute to accelerated tumor growth.

Loss of ZNRF3/RNF43 unleashes EGFR in cancer

fy2111@nyu.edu (Amy T Ku) — Fri, 10 Apr 2026 00:00:00 +0000

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data suggest ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptors, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer.

Uev1A counteracts oncogenic Ras stimuli in both polyploid and diploid cells

hrzhang@nankai.edu.cn (Dongze Song) — Wed, 25 Mar 2026 00:00:00 +0000

Oncogenic Ras is known to induce DNA replication stress, leading to cellular senescence or death. In contrast, we found that it can also trigger polyploid Drosophila ovarian nurse cells to die by inducing aberrant division stress. To explore intrinsic protective mechanisms against this specific form of cellular stress, here, we conducted a genome-wide genetic screen and identified the E2 enzyme Uev1A as a key protector. Reducing its expression levels exacerbates the nurse cell death induced by oncogenic Ras, while overexpressing it or its human homologs, UBE2V1 and UBE2V2, mitigates this effect. Although Uev1A is primarily known for its non-proteolytic functions, our studies demonstrate that it collaborates with the E3 APC/C complex to mediate the proteasomal degradation of Cyclin A, a key cyclin that drives cell division. Furthermore, Uev1A and UBE2V1/2 also counteract oncogenic Ras-driven tumorigenesis in diploid cells, suppressing the overgrowth of germline tumors in Drosophila and human colorectal tumor xenografts in nude mice, respectively. Remarkably, elevated expression levels of UBE2V1/2 correlate with improved survival rates in human colorectal cancer patients harboring oncogenic KRAS mutations, indicating that their upregulation could represent a promising therapeutic strategy.

The 1000⁺ mouse project for large-scale spatiotemporal parametrization and modeling of preclinical cancer immunotherapies

taylorn4@mail.nih.gov (Adam L Kenet) — Tue, 24 Mar 2026 00:00:00 +0000

Preclinical studies of chimeric antigen receptor (CAR)-T cell immunotherapies are often based on monitoring bioluminescent tumors implanted in mice to assess anti-tumor cytotoxicity. Here, we introduce maRQup (murine automatic Radiance Quantification and parametrization), an easy-to-use method that automatically processes bioluminescent tumor images for quantitative analysis. We demonstrate the ability of maRQup to analyze CAR-T cell treatments over >1000 tumor-bearing mice. We compare CD19-targeting CAR-T cells comprising either a CD28 or a 4-1BB costimulatory domain, and found the former controlled the tumor burden better initially, while the latter reduced the frequency of tumor relapse. We also applied maRQup to demonstrate faster tumor growth during the initial growth phase as compared to the relapse phase and to spatiotemporally analyze the high variability in immunotherapeutic control of tumors, based on their anatomical location. maRQup provides quantitative and statistically-robust insights on preclinical experiments that will contribute to the optimization of immunotherapies.

Blocking SHP2 benefits FGFR2 inhibitor and overcomes its resistance in FGFR2-amplified gastric cancer

taoshi@smail.nju.edu.cn (Hanbing Wang) — Mon, 23 Mar 2026 00:00:00 +0000

Fibroblast growth factor receptor 2 (FGFR2) is an important member of receptor tyrosine kinase (RTK) family. FGFR2 amplification occurs at a high frequency in gastric cancer (GC) and has been proven to be closely associated with poor prognosis and insensitivity to chemotherapy or immunotherapy. Current FGFR2-targeted therapies have limited efficacy. Hence, how to enhance efficacy and reverse resistance are urgent problems clinically. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) serves as the shared downstream mediator of all RTKs and a prominent immunosuppressive molecule. In this study, we identified FGFR2 amplification in 6.2% (10/161) of GC patients in our center. Then we showed that dual blocking SHP2 and FGFR2 enhanced the effects of FGFR2 inhibitor (FGFR2i) in FGFR2-amplified GC both in vitro (human GC cell lines) and in vivo (mouse xenograft tumor models) via suppressing RAS/ERK and PI3K/AKT pathways. We further showed that it overcame FGFR2i resistance by reversing the feedback activation mediated by other RTKs and continuously suppressing FGFR2-initiated downstream pathways. Notably, SHP2 blockade could suppress PD-1 expression and promoted IFN-γ secretion of CD8⁺ T cells, enhancing the cytotoxic functions of T cells in tumor immune microenvironment. Overall, our findings suggest that dual blocking SHP2 and FGFR2 is a compelling rationale with both targeted treatment and immune regulation for FGFR2-amplified GC.

p53-induced RNA-binding protein ZMAT3 inhibits transcription of a hexokinase to suppress mitochondrial respiration in human cancer cells

ashish.lal@nih.gov (Ashish Lal) — Tue, 17 Mar 2026 00:00:00 +0000

The tumor suppressor p53 is a transcription factor that controls the expression of hundreds of genes. Emerging evidence indicates that the p53-induced RNA-binding protein ZMAT3 acts as a key splicing regulator that contributes to p53-dependent tumor suppression in vitro and in vivo. However, the mechanism by which ZMAT3 functions within the p53 pathway remains largely unclear. Here, we discovered a function of ZMAT3 in inhibiting transcription of HKDC1, a hexokinase that regulates glucose metabolism and mitochondrial respiration in human cancer cells. Quantitative proteomics revealed HKDC1 as the most significantly upregulated protein in ZMAT3-depleted colorectal cancer cells. ZMAT3 depletion resulted in increased mitochondrial respiration, which was rescued by simultaneous depletion of HKDC1, suggesting that HKDC1 is a critical downstream effector of ZMAT3. Unexpectedly, ZMAT3 did not bind to HKDC1 RNA or DNA; however, proteomic analysis of the ZMAT3 interactome identified its interaction with the oncogenic transcription factor JUN. ZMAT3 depletion enhanced JUN binding to the HKDC1 locus, leading to increased HKDC1 transcription that was rescued upon JUN depletion, suggesting that JUN activates HKDC1 transcription in ZMAT3-depleted cells. Collectively, these findings uncover a mechanism by which ZMAT3 regulates transcription through JUN and demonstrate that HKDC1 is a key component of the ZMAT3-regulated transcriptome in the context of mitochondrial respiration regulation.

Synthetic gene circuits that selectively target RAS-driven cancers

kobi.benenson@gmail.com (Gabriel Valentin Senn) — Tue, 24 Feb 2026 00:00:00 +0000

Therapies targeting mutated rat sarcoma (RAS), the most frequently mutated oncogene in human cancers, could benefit millions of patients. Recently approved RAS inhibitors represent a breakthrough but are limited to a specific KRAS^G12C mutation and prone to resistance. Synthetic gene circuits offer a promising alternative by sensing and integrating cancer-specific biomolecular inputs, including mutated RAS, to selectively express therapeutic proteins in cancer cells. A key challenge for these circuits is achieving high cancer selectivity to prevent toxicity in healthy cells. To address this challenge, we present a novel approach combining multiple RAS sensors into RAS-targeting gene circuits, which allowed us to express an output protein in cells with mutated RAS with unprecedented selectivity. We implemented a modular design strategy and modeled the impact of individual circuit components on output expression. This enabled cell-line-specific adaptation of the circuits to optimize selectivity and fine-tune expression. We further demonstrate the targeting capabilities of the circuits by employing them in different RAS-driven cancer cells and provide evidence for their therapeutic potential by linking them to the expression of a clinically relevant output protein, which induced robust killing of cancer cells with mutated RAS. This work highlights the potential of synthetic gene circuits as a novel therapeutic strategy for RAS-driven cancers, advancing the application of synthetic biology in oncology.

Correction: BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling

Thu, 19 Feb 2026 00:00:00 +0000

Single-cell atlas of AML reveals age-related gene regulatory networks in t(8;21) AML

georges.lacaud@manchester.ac.uk (Georges Lacaud) — Wed, 11 Feb 2026 00:00:00 +0000

Acute myeloid leukemia (AML) is characterized by cellular and genetic heterogeneity, which correlates with clinical course. Although single-cell RNA sequencing (scRNA-seq) reflects this diversity to some extent, the low sample numbers in individual studies limit the analytic potential when comparing specific patient groups. We performed large-scale integration of published scRNA-seq datasets to create a unique single-cell transcriptomic atlas for AML (AML scAtlas), totaling 748,679 cells, from 159 AML patients and 51 healthy donors from 20 different studies. This is the largest single-cell data resource for human AML to our knowledge, publicly available at https://cellxgene.cziscience.com/collections/071b706a-7ea7-47a4-bddf-6457725839fc. This AML scAtlas allowed investigations into 20 patients with t(8;21) AML, where we explored the clinical importance of age, given the in-utero origin of pediatric disease. We uncovered age-associated gene regulatory network (GRN) signatures, which we validated using bulk RNA sequencing data to delineate distinct groups with divergent biological characteristics. Furthermore, using an additional multiomic dataset (scRNA-seq and scATAC-seq), we validated our initial findings and created a de-noised enhancer-driven GRN reflecting the previously defined age-related signatures. Applying integrated data analysis of the AML scAtlas, we reveal age-dependent gene regulation in t(8;21) AML, potentially reflecting immature/fetal HSC origin in prenatal origin disease vs postnatal origin. Our analysis revealed that BCLAF1, which is particularly enriched in pediatric AML with t(8;21) of inferred in-utero origin, is a promising prognostic indicator. The AML scAtlas provides a powerful resource to investigate molecular mechanisms underlying different AML subtypes.

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1⁺ TAMs

zzhang@shsci.org (Chongyi Jiang) — Mon, 09 Feb 2026 00:00:00 +0000

Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effect in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages, and citalopram treatment enhances local macrophage phagocytosis and elicits CD8⁺ T anti-tumor immunity. C5aR1 deficiency or depletion of CD8⁺ T cells hinders the anti-HCC effects of citalopram. Collectively, our study reveals the immunomodulatory roles of citalopram in inducing anti-tumor immunity and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.

Repression of PRMT activities sensitize human homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment

linzhang@pennmedicine.upenn.edu (Bingwei Wang) — Tue, 03 Feb 2026 00:00:00 +0000

Therapeutic epigenetic modulation is currently being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARP inhibitors. To broaden its clinical applicability and identify more effective combination strategies, we conducted a drug screen combining PARP inhibitors with 74 well-characterized epigenetic modulators targeting five major classes of epigenetic enzymes. Notably, both type I PRMT inhibitors and PRMT5 inhibitors scored highly in combination efficacy and clinical prioritization. PRMT inhibition significantly enhanced PARP inhibitor-induced DNA damage in human HR-proficient ovarian and breast cancer cells. Mechanistically, PRMT suppression downregulates DNA damage repair genes and BRCAness-associated pathways, while also modulating intrinsic innate immune responses within cancer cells. Integrative analysis of large-scale genomic and functional datasets from TCGA and DepMap further supports PRMT1, PRMT4, and PRMT5 as promising therapeutic targets in oncology. Importantly, dual inhibition of PRMT1 and PRMT5 synergistically sensitizes tumors to PARP inhibitors. Collectively, our findings provide strong rationale for the clinical development of PRMT and PARP inhibitor combinations in HR-proficient ovarian and breast cancers.

Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function

rongze.lu@ucsf.edu (Adaeze Scholastical Gbufor) — Thu, 29 Jan 2026 00:00:00 +0000

The rapid and sustained proliferation of cancer cells necessitates increased protein production, which, along with their disrupted metabolism, elevates the likelihood of translation errors. Ribosome-associated quality control (RQC), a recently identified mechanism, mitigates ribosome collisions resulting from frequent translation stalls. However, the precise pathophysiological role of the RQC pathway in oncogenesis remains ambiguous. Our research centered on the pathogenic implications of mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing), a specific RQC response to translational arrest on the outer mitochondrial membrane, in human glioblastoma multiforme (GBM). The presence of msiCAT-tailed mitochondrial proteins was observed commonly in glioblastoma stem cells (GSCs). The exogenous introduction of the mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein, accompanied by artificial CAT-tail mimicking sequences, enhanced mitochondrial membrane potential (ΔΨm) and inhibited the formation of the mitochondrial permeability transition pore (MPTP). These alterations in mitochondrial characteristics provided resistance to staurosporine (STS)-induced apoptosis in GBM cells. Consequently, msiCAT-tailing can foster cell survival and migration, whereas blocking msiCAT-tailing via genetic or pharmacological intervention can impede GBM cell overgrowth.

Robust assessment of asymmetric division in colon cancer cells

mattia.miotto@roma1.infn.it (Chiara Giannattasio) — Fri, 23 Jan 2026 00:00:00 +0000

Asymmetric partition of fate determinants during cell division is a hallmark of cell differentiation. Recent work suggested that such a mechanism is hijacked by cancer cells to increase both their phenotypic heterogeneity and plasticity and, in turn, their fitness. To quantify fluctuations in the partitioning of cellular elements, imaging-based approaches are used, whose accuracy is limited by the difficulty of detecting cell divisions. Our work addresses this gap, proposing a general method based on high-throughput flow cytometry measurements coupled with a theoretical framework. We applied our method to a panel of both normal and cancerous human colon cells, showing that different kinds of colon adenocarcinoma cells display very distinct extents of fluctuations in their cytoplasm partition, explained by an asymmetric division of their size. To test the accuracy of our population-level protocol, we directly measure the inherited fractions of cellular elements from extensive time lapses of live-cell laser scanning microscopy, finding excellent agreement across the cell types. Ultimately, our flow cytometry-based method promises to be accurate and easily applicable to a wide range of biological systems where the quantification of partition fluctuations would help account for the observed phenotypic heterogeneity and plasticity.

GMCL1 controls 53BP1 stability and modulates taxane sensitivity

anm4031@med.cornell.edu (Antonio Marzio) — Mon, 19 Jan 2026 00:00:00 +0000

Mitotic surveillance pathways monitor the duration of mitosis (M phase) in the cell cycle. Prolonged M phase, caused by spindle attachment defects or microtubule-targeting drugs, triggers formation of the ternary ‘mitotic stopwatch pathway’ complex (MSP) consisting of 53BP1, USP28, and p53. This complex stabilizes p53, leading to cell cycle arrest or apoptosis in daughter cells. In cancers that are resistant to paclitaxel, a microtubule-targeting agent, cells bypass mitotic surveillance activation, allowing unchecked proliferation, although the underlying mechanisms remain poorly understood. Here, we identify GMCL1 as a key negative regulator of MSP signaling. We show that 53BP1 physically interacts with GMCL1, but not its paralog GMCL2, and we map their interaction domains. CRL3^GMCL1 functions as a ubiquitin ligase that targets 53BP1 for degradation during the M phase, thereby reducing p53 accumulation in daughter cells. Depletion of GMCL1 inhibits cell cycle progression upon release from prolonged mitotic arrest, a defect that is rescued by co-silencing 53BP1 or USP28. Moreover, GMCL1 depletion sensitizes cancer cells to paclitaxel in a p53-dependent manner. Together, our findings support a model in which dysregulated CRL3^GMCL1-mediated degradation of 53BP1 prevents proper MSP function, leading to p53 degradation and continued proliferation. Targeting GMCL1 may, therefore, represent one possible avenue for addressing paclitaxel resistance in cancer cells with functional p53.

Lipid balance and chemoresistance in cancer cells

ynakamur@rs.tus.ac.jp (Kaori Kanemaru) — Mon, 12 Jan 2026 00:00:00 +0000

A shift in the balance between two lipids – cholesterol and sphingomyelin – makes hybrid epithelial-mesenchymal cancer cells less responsive to certain chemotherapy drugs.

Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia

tr2726@cumc.columbia.edu (Emily Diaz) — Wed, 07 Jan 2026 00:00:00 +0000

Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML), the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here, we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, increased lethality, and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase POLRMT and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.

Replication stress-inducing ELF3 upregulation promotes BRCA1-deficient breast tumorigenesis in luminal progenitors

xiaozhou@pku.edu.cn (Jiadong Wang) — Wed, 07 Jan 2026 00:00:00 +0000

BRCA1 is a critical tumor suppressor, mutations in which greatly increase risks for many tumors in carriers, most notably breast cancer. Luminal progenitor cells (LPs) are the currently recognized cells of origin of BRCA1-deficient breast cancers. However, the reason why LPs are prone to transform with BRCA1 deficiency has not been elucidated. Here, using single-cell sequencing of human BRCA1 mutant breast cancers and RNA sequencing (RNA-seq) of BRCA1-deficient normal mammary cells, we reveal that replication stress is a feature of LPs and a driving factor during BRCA1-associated tumorigenesis. Mechanistically, replication stress and BRCA1 deficiency lead to significant upregulation of ELF3 expression. ELF3 can help suppress excessive genomic instability and promote LP transformation with BRCA1 deficiency. Moreover, ELF3 emerged as a core transcription factor regulating LP genes, leading to LP expansion. Our findings suggest that replication stress is a driving factor during BRCA1-associated tumorigenesis in luminal progenitor cells and elucidates the key role of ELF3 during this process.

Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer

hy2602@cumc.columbia.edu (Eugene Son) — Mon, 29 Dec 2025 00:00:00 +0000

CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are standard for hormone receptor-positive (HR⁺) metastatic breast cancer. However, most patients eventually develop resistance and discontinue treatment, and there is currently no consensus on effective second-line strategies. Using preclinical HR⁺ human breast cancer models with acquired resistance to CDK4/6i, we demonstrate that maintaining CDK4/6i therapy, either alone or combined with CDK2 inhibitors (CDK2i), slows the growth of resistant tumors by prolonging G1 progression. Mechanistically, sustained CDK4/6 blockade in drug-resistant cells reduces E2F transcription and delays G1/S via a noncanonical, posttranslational regulation of retinoblastoma protein (Rb). Durable suppression of both CDK2 activity and growth of drug-resistant cells requires co-administration of CDK2i with CDK4/6i. Moreover, cyclin E overexpression drives resistance to the combination of CDK4/6i and CDK2i. These findings elucidate how continued CDK4/6 blockade constrains resistant tumors and support clinical strategies that maintain CDK4/6i while selectively incorporating CDK2i to overcome resistance.

Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females

anakk@illinois.edu (Angela E Dean) — Mon, 29 Dec 2025 00:00:00 +0000

Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate with survival outcomes for HCC patients. Gene signatures unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes and promotes liver tumorigenesis in females that, intriguingly, coincides with increased serum bile acid (BA) levels. Despite similar genetics, knockout male mice displayed higher serum BA concentrations, while female knockouts excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC.

Slowing the growth of drug-resistant tumors

yingyi_zhang@tju.edu.cn (Qianying Lu) — Thu, 18 Dec 2025 00:00:00 +0000

Using drugs that inhibit enzymes called CDK4/6 and CDK2 extends the G1 phase of the cell cycle and helps to slow the growth of drug-resistant breast cancer.

Multi-gradient permutation survival analysis identifies mitosis and immune signatures steadily associated with cancer patient prognosis

li_fei@fudan.edu.cn (Fei Li) — Wed, 17 Dec 2025 00:00:00 +0000

The inconsistency of the association between genes and cancer prognosis is often attributed to many variables that contribute to patient survival. Whether there exist the Genes Steadily Associated with Prognosis (GEARs) and functions remains largely elusive. Here, we developed a novel method named ‘Multi-gradient Permutation Survival Analysis’ (MEMORY) to screen the GEARs by using RNA-seq data from the TCGA database. We employed a network construction approach to identify hub genes from GEARs and utilized them for cancer classification. In the case of lung adenocarcinoma (LUAD), the GEARs were found to be related to mitosis. Our analysis suggested that LUAD cell lines carrying PIK3CA mutations exhibit increased drug resistance. For breast invasive carcinoma (BRCA), the GEARs were related to immunity. Further analysis revealed that CDH1 mutation might regulate immune infiltration through the EMT process. Moreover, we explored the prognostic relevance of mitosis and immunity through their respective scores and demonstrated it as valuable biomarkers for predicting patient prognosis. In summary, our study offered significant biological insights into GEARs and highlights their potentials as robust prognostic indicators across diverse cancer types.

Endoscopic liquid biopsies of gastric fluid in a large human patient cohort reveal DNA content as a candidate tumor biomarker in gastric cancer

wa116@rutgers.edu (Adriana P Bueno) — Tue, 16 Dec 2025 00:00:00 +0000

Gastric cancer remains a diagnostic and therapeutic challenge worldwide. Improved prognostic biomarkers could aid treatment planning across surgical, neoadjuvant, and adjuvant settings. We evaluated a novel liquid-biopsy approach integrated with esophagogastroduodenoscopy (EGD) by analyzing gastric fluid DNA (gfDNA) from a large cohort (n=1056) to assess its diagnostic utility and prognostic value in gastric cancer. In this exploratory study, gfDNA concentration was measured in patients with normal gastric mucosa, peptic diseases, preneoplastic conditions, or cancer. Variables included sex, gastric fluid pH, proton-pump inhibitor use, tumor subtype, stage, and outcomes. gfDNA levels were significantly higher in gastric cancer than in all comparison groups (mean 26.86 ng/µL; 95% CI 20.05–33.79; p=3.61 × 10e^-12) and as compared to non-malignant controls (mean 10.77 ng/µL; 95% CI 9.23–12.33; p=9.55 × 10e^-13) and preneoplastic states (mean 10.10 ng/µL; 95% CI 7.59–12.60; p=1.10 × 10e^-5). Advanced tumors (T3) exhibited higher gfDNA than earlier stages (T2 or below; mean 25.66 vs 15.12 ng/µL; p=5.97 × 10e^-4). In a subset of gastric cancer patients, gfDNA >1.28 ng/µL associated with longer progression-free survival (p=0.009) and correlated with increased tumor-infiltrating immune cells (p=0.001); this association remained after adjusting for stage (p=0.014). Elevated gfDNA supports gastric cancer presence in the general human population and may inform disease management when combined with tissue biopsies. Importantly, gfDNA shows prognostic potential in established gastric cancer, where higher gfDNA content may paradoxically relate to better outcomes, potentially linked to immune-cell infiltration. These findings warrant further validation and integration with complementary diagnostic modalities to enhance accuracy and clinical utility.

Transcriptional subtypes on immune microenvironment and predicting postoperative recurrence and metastasis in human pheochromocytoma and paraganglioma

lilingyu@jlu.edu.cn (Fengrui Nan) — Tue, 16 Dec 2025 00:00:00 +0000

Human pheochromocytomas and paragangliomas (PPGLs) exhibit substantial molecular and immune heterogeneity, complicating risk assessment and treatment. Here, we define three distinct tumor transcriptional subtypes (C1, C2, and C3) in a clinically annotated cohort of PPGL patients through integrative transcriptomic and immunogenomic profiling. C1 is characterized by hypoxia-driven pathways and an immunosuppressive microenvironment, correlating with poor prognosis. C2 exhibits a highly inflamed immune landscape with robust CD8⁺ T cell infiltration, suggesting potential sensitivity to immunotherapy. C3 is enriched in metabolic reprogramming pathways and displays intermediate clinical outcomes. Genetic analysis reveals subtype-specific mutational patterns, with pseudohypoxic driver mutations (SDHB, VHL, SDHA, and SDHD) predominant in C1 and C3, while kinase pathway alterations (NF1 and RET) define C2. Single-nucleus RNA sequencing of human PPGL tumors further delineates immune ecosystem diversity. Notably, we identify ANGPT2, PCSK1N, and GPX3 as key subtype-specific biomarkers, with ANGPT2 driving tumor progression in C1 and emerging as a potential therapeutic target. Our findings provide a refined molecular classification integrating immune and genomic features in human PPGLs, offering a framework for improved prognostication and precision therapies in this rare neuroendocrine tumor type.

Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics

inbalavr@gmail.com (Anezka Niesnerova) — Fri, 12 Dec 2025 00:00:00 +0000

While advances in single-cell genomics have helped to chart the cellular components of tumor ecosystems, it has been more challenging to characterize their specific spatial organization and functional interactions. Here, we combine single-cell RNA-seq, spatial transcriptomics by Slide-seq, and in situ multiplex RNA analysis to create a detailed spatial map of healthy and dysplastic colon cellular ecosystems and their association with disease progression. We profiled inducible genetic CRC mouse models that recapitulate key features of human CRC, assigned cell types and epithelial expression programs to spatial tissue locations in tumors, and computationally used them to identify the regional features spanning different cells in the same spatial niche. We find that tumors were organized in cellular neighborhoods, each with a distinct composition of cell subtypes, expression programs, and local cellular interactions. Comparing to scRNA-seq and bulk RNA-seq data from human CRC, we find that both cell composition and layout features were conserved between the species, with mouse neighborhoods correlating with malignancy and clinical outcome in human patient tumors, highlighting the relevance of our findings to human disease. Our work offers a comprehensive framework that is applicable across various tissues, tumors, and disease conditions, with tools for the extrapolation of findings from experimental mouse models to human diseases.