Glioblastoma cell plasticity: A new paradigm in glioblastoma therapeutic resistance.

Fatty acid synthase (FASN), the key enzyme driving de novo lipogenesis, has emerged as a central metabolic hub in cancer, linking aberrant lipid synthesis to tumor progression, immune escape, and therapy resistance. This review provides a comprehensive overview of the regulatory landscape and oncogenic functions of FASN, highlighting its modulation at transcriptional, post-transcriptional, and post-translational levels. We discuss how FASN-driven lipid remodeling supports tumor proliferation, disrupts antigen presentation, alters immune cell metabolism, and suppresses ferroptosis, thereby enabling resistance to chemotherapy, radiotherapy, targeted therapy, and immune checkpoint inhibitors. Emerging therapeutic strategies-including direct FASN inhibition, targeting upstream regulators, and rational metabolic-immune-ferroptosis combinatorial regimens-are explored in the context of precision oncology. Given the metabolic plasticity of cancer cells and the heterogeneous response of the tumor immune microenvironment, future advances will rely on dynamic biomarker-guided therapy and spatiotemporal profiling of FASN activity. Together, these insights position FASN not merely as a metabolic enzyme but as a versatile therapeutic axis at the intersection of cancer metabolism, immunity, and resistance.

Decoding plant cell heterogeneity and dynamics across responses, development, to evolution with single-cell technologies.

Tgfbr2 deficiency promotes mitochondrial dysfunction of vascular smooth muscle cells in thoracic aortic aneurysms and dissections.

Abstract Circulating tumor cells (CTCs) provide a minimally invasive window into cancer biology and metastatic progression. However, their phenotypic heterogeneity extends beyond classical epithelial marker expression to include subsets with immune features. Using high-resolution single-cell genomic and proteomic profiling of peripheral blood from patients with stage 4 breast cancer, we identified a distinct population of immune-like CTCs (im.CTCs) that co-express epithelial and immune markers, including CD45, CD3, and CD4. These im.CTCs share clonal, tumor-specific genomic alterations with canonical epithelial CTCs, indicating a non-fusion origin and supporting the existence of a previously unrecognized tumor cell plasticity state. We further observed direct physical interactions between circulating white blood cells, predominantly CD4+ T cells, and both im.CTCs and immune marker–positive large extracellular vesicles (im.LEVs) in patient blood samples. Immune membrane markers were enriched at sites of cell–cell contact, consistent with membrane transfer as a mechanism by which tumor-derived circulating analytes acquire immune features. Together, these findings demonstrate that tumor–immune cell interactions in circulation contribute to the emergence of hybrid phenotypes among circulating tumor analytes. This phenomenon has important implications for liquid biopsy interpretation, immune modulation, and the biology of metastatic dissemination. Future work will be required to define the functional consequences of immune marker expression on CTCs and extracellular vesicles and to determine how these interactions influence immune surveillance, metastatic potential, and clinical outcomes. Citation Format: Stephanie N. Shishido, Peter Kuhn, James Hicks, Nikki Higa, Amin Naghdloo, Mohamed Kamal, Dean Tessone, Valerie Hennes, Audrey Limb, Andres Rivera, Rafael Nevarez, Anand Kolatkar, Carol K. Tweed, Adam I. Riker, Young Lee, Lorraine Tafra, Jeremy Perkins, Craig D. Shriver. Immune-Like Circulating Tumor Cells and Large Extracellular Vesicles in Metastatic Breast Cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-C012.

Small cell lung cancer (SCLC), accounting for ~15% of lung cancers, is an aggressive and lethal tumor type. It is characterized by rapid proliferation, early metastasis, and poor prognosis. Current therapies, including platinum-based chemotherapy and recently introduced immune checkpoint inhibitors, provide modest survival benefits due to frequent relapse and therapeutic resistance. At the molecular level, SCLC is marked by near-universal loss of the tumor suppressors genes TP53 and RB1, and exhibits marked heterogeneity driven by several key master transcription factors. These factors define distinct molecular subtypes with unique gene expression programs and therapeutic vulnerabilities, enabling cell plasticity and subtype switching in response to treatment pressures. A thorough understanding of these subtype-specific dependencies and the epigenetic mechanisms regulating transcription is critical for developing effective and durable therapies. This review focuses on these aspects and evaluates the potential of epigenetic-targeted strategies in the treatment of SCLC.

Chronic Morphine Differentially Impacts Glutamatergic Synaptic Plasticity in the Ventral Tegmental Area of Adult versus Adolescent Mice.

Context-dependent effect of glucocorticoid receptor activity shapes ovarian cancer cell plasticity and therapy response.

Hirschsprung disease (HSCR) is a congenital condition featuring aganglionosis in the distal colon, causing functional obstruction. While EGF and bFGF are well-characterized neurogenic factors, the precise mechanistic role of GDNF in modulating enteric glial cell plasticity remains incompletely understood. EGCs were identified via proteomic profiling and immunofluorescence in Ednrb⁻/⁻ mice modeling HSCR. EGC/PK060399egfr and primary EGCs were induced with neural stem cell-inducing medium (NSC-Med). Morphological changes, EdU assay, immunofluorescence, RT‒qPCR, and Western blotting were employed to assess the expression of stemness- and neuron-associated markers. Metabolomic and transcriptomic analyses were performed to evaluate metabolic remodeling and signaling pathways. Following treatment with NSC-Med, immunofluorescence analysis revealed that neurospheres expressed high proportions of Nestin-positive (97.09%), Sox2-positive (50.11%), and p75NTR-positive (77.87%) cells. Metabolomic profiling revealed a significant enhancement of the Warburg effect in the NSC-Med group. Western blot analysis further revealed elevated expression of PKM2, along with significant increases in both extracellular and intracellular lactate levels following NSC-Med treatment. NSC-Med treatment significantly enhanced proliferation, as demonstrated by a 2.3-fold increase in EdU incorporation (P < 0.05). Transcriptomic analysis revealed the activation of the calcium signaling pathway in the GDNF group. Western blotting revealed a significant increase in CaMKII phosphorylation, and treatment with the calcium chelator BAPTA-AM attenuated GDNF-induced NeuroD1 upregulation. NSC-Med promotes stem cell-associated features and gene expression in enteric glial cells. GDNF-a key component of NSC-Med-activates a neurogenic cascade via the calcium signaling pathway (CaMKII-NeuroD1 axis), which offers a potential targeted molecular strategy for HSCR therapy.

The genomic plasticity of Chinese Hamster Ovary cells allows them to be genetically engineered to produce foreign proteins with high specific productivities while placing a significant burden on their ability to retain this expression capacity over time. Many cell lines lose expression over time and need to be screened for expression consistency. Stability has been studied in clonally derived cell cultures by evaluating phenotypic heterogeneity in subclones derived from stable or unstable clones, but not well characterized within the primary, clonally derived cell culture. To address this, we employed single cell RNA sequencing in stable and unstable cell lines expressing the same monoclonal antibody, at early and late timepoints in their manufacturing lifespan. We observed higher expression heterogeneity and a more drastic redistribution of expression profile "clusters" over serial passaging in the unstable cell line. Differentially expressed genes in those clusters making up the unstable cell line suggest distinct changes in metabolic pathway activity in this cell line over time. Using molecular methods, changing gene expression profiles were confirmed and activation of molecular pathways consistent with a challenged protein homeostasis were shown to be enriched in cells over time in the unstable cell line. This report more broadly implicates the role of heterogeneity within a clonal population as a contributing factor to cell line instability, providing a biological context for further investigation.

Trigeminal neuralgia (TN) is a debilitating neuropathic pain disorder characterized by severe paroxysmal facial pain. Increasing evidence indicates that Schwann cell dysfunction and altered nerve repair mechanisms contribute to TN pathology. MicroRNAs (miRNAs), as key regulators of Schwann cell plasticity, myelination, inflammation, and nerve regeneration, represent promising biomarker candidates. This study aimed to investigate differential expression patterns of Schwann cell-associated miRNAs (miR-221-3p, miR-132-3p, miR-210-5p, miR-340-3p, miR-98-5p, miR-182-5p) in patients with trigeminal neuralgia and evaluate their diagnostic biomarker potential. Expression analysis was performed using quantitative real-time PCR with 5s rRNA as the reference gene. miRNA expression levels were evaluated by qRT-PCR. Differential expression was calculated using ΔCt, ΔΔCt, and fold-change analyses. Diagnostic performance was assessed using ROC curve analysis. Integrated visualization was carried out using scatter plots, volcano plots, and z-score-normalized heatmaps. miR-221-3p was significantly upregulated in patients with trigeminal neuralgia (TN), whereas miR-340-3p and miR-182-5p were downregulated. Hierarchical clustering and principal component analysis (PCA) demonstrated a clear separation between patient and control miRNA expression profiles. In receiver operating characteristic (ROC) analyses, miR-221-3p emerged as the most powerful individual biomarker (AUC = 0.699), while the combined miRNA panel achieved high diagnostic performance (AUC = 0.89). Downregulated miRNAs reflect suppressed inhibitory signaling pathways, suggesting that miRNA profiling may provide valuable insights into Schwann cell pathology in TN. The selected miRNAs, which are implicated in impaired Schwann cell repair mechanisms, represent promising molecular biomarker candidates for the diagnosis of TN and potentially for guiding therapeutic strategies.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by sustained synovial inflammation contributing to bone erosion and loss of joint function. The pathological response of infiltrated T cell subsets, followed by the formation of ectopic lymphoid microstructures in the synovial tissue, promotes RA progression and exacerbates disease severity. Two major hallmarks of RA pathogenesis are dysregulated peripheral tolerance and aberrant pro-inflammatory responses due to the secretion of pro-inflammatory cytokines within the RA synovium. Interestingly, regulatory T cells (Tregs) and Th2, which play a vital role in maintaining immune homeostasis and peripheral tolerance, are reduced in numbers or become functionally impaired within the RA synovium, resulting in Th1/Th2 and Th17/Treg imbalance. Additionally, CD8+ T cells have also emerged as major mediators of synovial inflammation and autoantibody production in RA. Women display higher susceptibility to developing RA, and the chances of disease pathogenesis increase steadily from menarche to menopause, possibly due to a decline in sex-hormone levels. Although the decline in female sex hormones has been implicated in aberrant T cell responses and RA progression, the impact of hormone levels on the molecular signaling pathways regulating T cell differentiation and homeostasis, and subsequently the disease pathogenesis in premenopausal and postmenopausal women, remains incompletely understood. Hence, this review aims to provide a comprehensive understanding of the differential control of sex hormone levels in regulating T cell responses, including T cell plasticity and functions associated with RA progression. We further discuss the underlying signaling mechanisms where declining postmenopausal sex-hormone levels promote aberrant T-cell activation and effector functions within the RA synovium, thereby disrupting peripheral tolerance and immune homeostasis, and contributing to RA pathogenesis. A critical understanding of sex hormone-mediated regulation of T cell responses associated with RA may unveil novel hormone-targeted therapeutic strategies to limit disease progression.

Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells.

Tumor-immune hybrid cell biology: A review of its potential impact in oncology.

Cell replacement therapies hold great promise for the treatment of type 1 diabetes mellitus; however, the obtaining of sufficient transplantable β-cells limits the availability of this treatment option. The generation of β-cells from human pluripotent stem cells or other somatic cells through classical differentiation, forward programming, or transdifferentiation approaches offers an alternative source of therapeutic β-cells for the treatment of type 1 diabetes mellitus. Through increasing understanding of pancreatic and β-cell development, transcription factors neurogenin 3 (NGN3), pancreas/duodenum homeobox protein 1 (PDX1), and MAF BZIP Transcription Factor A (MAFA) have been identified to be crucial for glucose-responsive insulin secretion of adult β-cells. In this review, we address and discuss recent advances in transdifferentiation approaches using these three markers for the timely generation of mature β-cells, and the insights they provide on cell development and plasticity.

Breast cancer progression is increasingly recognized as an immunometabolic disorder in which tumor-intrinsic metabolic reprogramming and microenvironmental stress converge to impair innate immune surveillance. Beyond its established role in glycemic control, metformin has emerged as a promising immunometabolic modulator with anticancer potential. Accumulating evidence indicates that metformin suppresses breast tumor growth by targeting key metabolic vulnerabilities, including dysregulated glycolysis, lipid metabolism, and mitochondrial energetics, while simultaneously restoring the functional competence of innate immune effectors, particularly natural killer (NK) and natural killer T (NKT) cells. At the molecular level, metformin engages AMP-activated protein kinase (AMPK)-centered signaling and mitochondrial complex I-associated energetic stress, leading to downstream modulation of mTOR activity, redox balance, autophagy, and RNA-mediated regulatory networks. These coordinated effects reduce tumor cell plasticity and enhance immune permissiveness. Within the tumor microenvironment, metformin attenuates hormone-dependent stromal support, disrupts immunosuppressive myeloid networks, normalizes chemokine and cytokine profiles, and promotes antigen presentation and innate immune cell recruitment. Preclinical studies consistently demonstrate delayed tumor onset, suppression of aggressive breast cancer subtypes, impairment of cancer stem cell maintenance, and reinforcement of NK/NKT-mediated antitumor surveillance following metformin treatment. However, emerging clinical and translational evidence suggests that therapeutic efficacy is context dependent, influenced by tumor molecular subtype, host metabolic status, immune composition, and pathway-specific biomarker engagement. This review critically synthesizes mechanistic, preclinical, and clinical findings to position metformin as a host-directed immunometabolic adjuvant in breast cancer. Integrating insights from metabolism, innate immunology, pharmacology, and biotechnology, this work highlights opportunities for biomarker-guided stratification and rational combination strategies aimed at enhancing NK/NKT-cell-driven antitumor immunity in breast cancer therapy.

Natural killer (NK) cells are critical regulators of immune balance at the maternal-fetal interface. T-bet (Tbx21) is a key transcription factor shaping NK cell effector functions, yet its role in decidual NK (dNK) cell adaptation across gestation remains unclear. We used a T-bet fate-mapping mouse model (Rosa26RFP × Tbx21Cre) to track developmental and functional reprogramming of NK cells in the uterus, decidua, and placenta throughout pregnancy. Analyses included flow cytometry, bulk RNA sequencing of fate-mapped cells, and single-cell transcriptomic profiling of CD45+Lineage- immune populations at mid and late gestation. We found that NK cells with a history of T-bet expression (RFP+) progressively downregulate T-bet in a tissue and gestation-specific manner, particularly within decidual and placental compartments. Despite this loss, RFP+ cells retained core NK cell markers and altered their lineage identity towards ILC2 or ILC3 fate. Bulk transcriptomic analysis revealed that T-bet downregulation is associated with dampened IFN-γ, and cytotoxic pathways and increased expression of tissue-residency associated transcriptional regulators. Single-cell RNAseq revealed a gestational transition in dNK subset composition, with a decline in cytotoxic tissue-resident NK cells and expansion of regulatory and conventional NK subsets by late gestation. These findings identify a novel transcriptional program that shapes NK cell plasticity in response to T-bet downregulation across gestation. Rather than undergoing lineage diversion, dNK cells adapt to the decidual environment via transcriptional compensation and subset redistribution during pregnancy. This work sheds light on the temporal coordination of innate immune function relevant to pregnancy success.

Leukemia stem cell (LSC) phenotyping offers significant potential to enhance minimal residual disease (MRD) monitoring in acute myeloid leukemia (AML), improving therapeutic evaluation and relapse prediction. However, current approaches lack the sufficient sensitivity and specificity to reliably detect rare chemotherapy-resistant LSCs (crLSCs) or identify stem-like phenotypic states, limiting clinical translation. Here, we develop DISCERN (Dual-Aptamer-Initiated Sensing Circuit via Engineered Nanozyme), a colorimetric platform for ultrasensitive LSC phenotyping. DISCERN employs a dual-aptamer system targeting colocalized surface markers (CD33 and CD123) for high-specificity recognition. Its exceptional sensitivity (limit of detection <10 cells/mL) is achieved by a localized catalytic cascade: target-binding initiates on-site rolling circle amplification (RCA), which in turn templates the assembly of PCN-222(Fe) nanozymes that generate amplified colorimetric signals. We demonstrate that DISCERN can track phenotypic plasticity in leukemia cells and identify stem-like subsets in leukemia xenograft models. This cost-effective and robust platform provides a promising tool for AML risk stratification, relapse prediction, and precision therapy.

In the complex landscape of cancer progression, the immune system shapes crucial interactions between tumor and immune cells. Understanding this dialogue is essential for elucidating how immune-derived cues trigger epithelial-mesenchymal transition (EMT)-like transcriptional changes, a fundamental process that drives tumor cell plasticity and facilitates aggressive phenotypes. Here, we investigated the crosstalk between M2 macrophages and colon cancer cells (HT-29) during the post-tumorigenic phase, focusing on exosome-mediated regulation of EMT, a critical pathway controlling tumor cell phenotypic and transcriptional dynamics. Co-culture experiments revealed that M2 macrophage-derived exosomes (M2-Exo) induced profound transcriptional changes, with downregulation of epithelial markers and increased expression of mesenchymal genes. Importantly, EMT induction was markedly stronger following M2-Exo treatment than in the co-culture setting, suggesting that while soluble mediators play a contributory role, EMT is predominantly and directly driven by exosome-mediated signaling. Transcriptomic profiling identified FAM83A as a key upregulated gene in M2-Exo-treated HT-29 cells. Functional analyses demonstrated that FAM83A promoted EMT by modulating regulators associated with decreased E-Cadherin and increased N-Cadherin, MMP2, and MMP9 expression. Importantly, siRNA-mediated silencing of FAM83A abolished its overexpression and inhibited EMT activation, confirming its essential role in M2-Exo-induced programming of EMT. Collectively, these findings highlight exosome-mediated immune-tumor interactions as critical drivers of EMT and the progression toward an invasive, mesenchymal-like phenotype.

Glioblastoma (GBM) remains one of the most lethal brain tumors, largely due to the resilience and plasticity of glioblastoma stem cells (GSCs), which drive tumor growth, recurrence, and resistance to conventional therapies. A key mechanism underlying their aggressiveness is transdifferentiation, whereby GSCs acquire endothelial- and pericyte-like phenotypes, promoting neovascularization and remodeling the tumor microenvironment to sustain malignancy. Conventional treatments often fail to eliminate these resilient populations, highlighting the need for innovative targeted strategies. Chimeric antigen receptor (CAR)-based immunotherapies offer a targeted strategy to specifically eliminate GSCs and interfere with their role in promoting tumor vascularization and suppressing immune responses. This review aims to provide a comprehensive overview of the molecular mechanisms driving GSC transdifferentiation and to summarize the current landscape of CAR-T therapies developed to target these cells. By integrating knowledge of GSC biology with advances in CAR-T-based interventions, this work highlights the potential of next-generation immunotherapies to overcome therapeutic resistance, limit tumor recurrence, and improve clinical outcomes in GBM.