Communications Biology最新文献

Radiotherapy (RT) is the standard-of-care for diffuse intrinsic pontine glioma (DIPG); however, it functions as a palliative treatment. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is upregulated in most DIPG tumors, posing a promising therapeutic target. Immunotherapies harnessing IL-13Rα2 to selectively deliver cytotoxic payloads such as pseudomonas exotoxin A (PE) are safe in DIPG patients and efficacious in preclinical disease models. Here, we used DIPG cell lines and mouse models to compare RT alone with RT plus the IL-13Rα2-targeted PE immunotoxin GB13 (IL13.E13K-PE4E). DNA strand breaks were evaluated by γH2AX and apoptosis, as well as other on-target effects, by Western blot and immunofluorescence. Cell viability and colony formation assays delineated cell viability and proliferation. In vivo efficacy was based on survival of mice with orthotopic tumors. Animals received fractionated focal irradiation and neoadjuvant and concomitant GB13 by convection-enhanced delivery. GB13 improved the efficacy of RT in vitro through inhibition of DNA damage repair and convergent modulation of apoptotic signaling. Combined RT and intratumoral administration of GB13 decreased tumor burden and prolonged survival in orthotopic xenograft and genetically engineered mouse models. These findings indicate that RT plus GB13 is well tolerated and effective, informing future investigation of a novel therapeutic approach for DIPG.

Genomes record past climatic impact on species' range shifts, admixture, refugial isolation, and adaptative evolution. However, these processes are poorly understood in perennial herbaceous species forming a dominant group of temperate flora. We present a demographic history of the perennial herb woodland strawberry (Fragaria vesca L.) reconstructed from 200 genomes spanning most of its European range. Temporal population structure reveals a strong division into western and eastern genetic clusters along a longitudinal climatic gradient, with eastern core populations showing greater resilience during glaciations. Divergence patterns indicate that postglacial recolonization of western and eastern Europe occurred from distinct refugia in multiple waves. The current largest, admixed populations from the Mediterranean to northern Europe form a continuous chain maintained by east-west gene flow through Central Europe, with historical migration patterns indicating comparable connections during earlier interglacials. Our reconstruction of woodland strawberry's climatic history with high temporal resolution reveals how the late Pleistocene core-periphery dynamics shaped its survival and genome evolution under climate change. The data points to populations that are essential for maintaining the long term genetic diversity of the species and opens new avenues to understand climatic adaptation of temperate flora.

The prognosis of relapsed or refractory acute myeloid leukemia (r/r AML) patients remains poor due to lack of novel therapies. We previous demonstrated that chimeric antigen receptor (CAR) T cells targeting CD64 have the potential to treat AML with minimal toxicity to hematopoietic stem/progenitor cells. However, the efficacy was limited in AML mouse models. Interleukin-15 (IL-15), a cytokine that promotes T cell survival and proliferation, has been shown to enhance CAR T cell activity. Here, we engineer CD64 CAR T cells with overexpression of IL-15 and evaluate the function. IL-15-armed CAR T cells exhibit enhanced cytolytic activity against AML cells, improve expansion and persistence in vitro, and favor a memory phenotype while reducing exhaustion and apoptosis. In mouse model, IL-15-armed CAR T cells show robust expansion, prolong mouse survival, and no obvious toxicity. These findings suggest that IL-15-armed CD64 CAR T cells may be a promising strategy for r/r AML.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic disease with multiple etiologies, stemming from the interplay between local and systemic genetic, diet, and gene-environment interactions. To understand the progression of MASLD in a controlled setting, we utilized a human liver microphysiological system (MPS) to establish a physiologically relevant metabolic baseline and probe how primary human hepatocytes respond to perturbations in insulin, glucose, and free fatty acids (FFAs). Replicate liver MPS were maintained in media with either 200 pM or 800 pM insulin for up to 3 weeks alone and in combination with standard glucose (5.5 mM), hyperglycemia (11 mM glucose), normal (20 µM) and elevated FFA (100 µM). Together, hyperinsulinemia along with elevated glucose and FFAs, induces the release of pro-inflammatory chemokines, accumulation of triglycerides, and predisposes hepatocytes to insulin resistance. Treatment with the thyroid receptor β agonist resmetirom normalizes hepatic fat content and partially rescues insulin sensitivity, but paradoxically induces higher CXCL1 and IL8 expression in male and female donors. In aggregate, our enhanced in vitro MPS model establishes a metabolic baseline and perturbed condition that recapitulates a spectrum of phenotypes observed in MASLD, offering improved quantification and insight into disease progression with relevance to human physiology.

WDR62, a centrosome and microtubule associated protein, regulates mitotic spindle formation and centrosome integrity in progenitor cells during development. While its role in neural progenitor differentiation is known, its function in myogenesis remains unclear. Here, we show that WDR62 deficient mice possess smaller skeletal muscles. Following cardiotoxin injury to the tibialis anterior muscle, WDR62 deficient mice show normal satellite cell activation, but display a higher percentage of immature myofibers at day 7 post injury, suggesting premature differentiation. In Drosophila larvae, Wdr62 knockdown in the wing disc increases asymmetric myoblast division resulting in premature differentiation. In C2C12 mouse myoblasts, WDR62 loss leads to decreased myoblast proliferation due to increased centriole numbers and centriole cohesion, and a slight increase in myoblast fusion at day 3 differentiation, which supports premature differentiation. These data implicate WDR62 in maintaining centrosome integrity that is critical for myoblast proliferation and preventing premature differentiation during early stages of myogenesis.

Conventional T cells recognize peptides presented by the human leukocyte antigen (HLA) proteins through their T cell receptors (TCRs). Given that thousands of HLA proteins have been discovered, each presenting thousands of different peptides, decoding the cognate HLA protein of a TCR experimentally is a challenging task. To address this problem, we combined statistical learning methods with a unique dataset of paired T cell repertoires and HLA allotypes for 6,794 individuals. This enabled us to discover 34,206 T cell receptor alpha (TRA) and 891,564 beta (TRB) clonotypes that were associated with 175 unique HLA alleles. The identified clonotypes target prevalent infections, e.g. influenza, cytomegalovirus and Epstein-Barr virus. Utilizing these clonotypes, we develop statistical models that impute the carriership of common HLA alleles from the TRA- or the TRB- repertoire. In conclusion, the identified allele-associated clonotypes encode the HLA fingerprints and the antigenic exposure history of individuals and populations.

Plasticity is a central mechanism underlying the robust regenerative capacity of the intestinal epithelium. Two major forms of plasticity have been described: spatial plasticity, in which differentiated cells revert to crypt base columnar cells (CBCs), and fetal reversion into revival stem cells (revSCs). However, the relationship among these two stem cell populations and differentiated cells remains to be clarified. Here, we demonstrated the bidirectional interconversion between CBCs and revSCs. Using lineage tracing, injury models and villus culture, we show that absorptive enterocytes can reprogram into revSCs and regenerate CBCs. These findings position fetal reversion as an entry point to spatial plasticity, establishing a regenerative hierarchy where CBCs, revSCs, and enterocytes collectively orchestrate intestinal repair. Furthermore, we identified revSCs as a highly stress-tolerant stem cell population, whose emergence would preserve the stem cell pool. Our results establish fetal reversion as a cellular escape mechanism safeguarding epithelial regeneration under inflammatory conditions.

Osteosarcoma lacks effective molecular targets, and the biological role of MAT2A in this disease remains unclear. Here we show that MAT2A drives osteosarcoma progression by increasing the transcription of the downstream gene PARN. MAT2A interacts with the transcription factor SRF, promotes its SUMO-dependent stabilization in the nucleus, and enhances its ability to activate PARN. A catalytically inactive MAT2A mutant retains this function, indicating a SAM-independent mechanism. MAT2A also elevates aerobic glycolysis in osteosarcoma cells through the PARN-PI3K-AKT pathway, while pharmacological inhibition of MAT2A reduces glycolysis, SRF and PARN expression, and tumor growth in vitro and in vivo. These findings identify a previously unrecognized regulatory mechanism linking MAT2A to transcriptional control and metabolic reprogramming, and highlight MAT2A as a promising therapeutic target for osteosarcoma.

Elucidating transcriptional regulatory mechanisms within tissues is essential for both physiological and pathological studies of giant panda. Here, we generate transcriptomic profiles and construct 3D genome maps for nine giant panda tissues. For the first time, we describe alterations in 3D genome organization among giant panda tissues, providing evidence for changes of A/B compartmentalization, variations in topologically associating domains, and rewiring of promoter-enhancer interactions. We demonstrate that many 3D genome reorganization events are tissue-specific and these structural changes are associated with tissue-specific expression of genes and tissue-relevant biological functions. Furthermore, we use these 3D genome maps to systematically interpret adaptive evolution in giant panda genome, emphasizing importance of considering the genome as a 3D configuration when dissecting potential functions of DNA sequence variation. Collectively, our study increases understanding of functional regulatory mechanisms of giant panda tissues and provides a foundational dataset for analysis of tissue-specific regulatory networks in giant panda.

Traditional structure-based pre-screen compound selection relies on the assumption that chemical similarity implies similar biological activity. This paradigm narrows the exploration of chemical space and often fails to account for functional convergence, where structurally diverse compounds act through distinct targets to produce similar phenotypic effects. As a result, compounds with therapeutic potential may be overlooked. To overcome this constraint, we introduce a training-free, transfer learning-based method for large scale compound preselection that leverages deep phenotypic profiling of human cells. Notably, this enables robust pairwise comparison of phenotypic signatures across any source of the entire JUMP-CP, the largest publicly available cell painting dataset (112,480 compounds), preserving biological signals while mitigating batch effects. Validated across 65 high-throughput assays-including in vitro and in cellulo systems-our method provides efficient pre-screen enrichment of biologically active compounds, bypassing the blind spots of structure-centric approaches. Interestingly, because it is large scale, it also allows for a comprehensive analysis of structure-phenotypic activity relationships, revealing potentially thousands of compound activity cliffs, where minimal chemical changes in structure may result in profound phenotypic shifts. We show that these cliffs capture subtle, atom-level determinants of bioactivity that cannot be accessed by structure-based models. Furthermore, we demonstrate that structurally diverse compounds targeting different genes in the same biological pathway can induce either convergent or opposite phenotypes-a phenomenon validated across 30 pathways, hundreds of genes, and thousands of compounds. Finally, to support the broader community, we propose Phenoseeker, a web-based tool enabling instant retrieval of JUMP-CP compounds with similar phenotypic profiles. Together, these findings position phenotypic profiling not merely as a complementary tool, but as a transformative and scalable framework for navigating chemical space through a biological lens. By capturing rich morphological signatures that reflect functional outcomes-regardless of structural similarity-this approach enables the discovery of bioactive compounds, novel mechanisms of action, and unexpected target-pathway relationships. Applied at the scale of the JUMP-CP dataset, phenotypic profiling emerges as a powerful strategy for prioritizing compounds, illuminating activity cliffs, and accelerating the identification of therapeutically relevant candidates across diverse biological contexts.