Oncogene, Published online: 04 April 2026; doi:10.1038/s41388-026-03742-8
Deciphering functional intra-tumoral heterogeneity in BRAFV600E-driven mouse thyroid cancer reveals EMT trajectory and metabolic remodeling
Nature Cancer, Published online: 03 April 2026; doi:10.1038/s43018-026-01141-2
Li et al. present PRET, a few-shot system for pan-cancer detection not requiring model fine-tuning, validated it in multicenter datasets and found that it outperformed existing approaches across tasks and pathologists in lymph node metastasis detection.
Res Sq [Preprint]. 2026 Mar 18:rs.3.rs-8913641. doi: 10.21203/rs.3.rs-8913641/v1.
ABSTRACT
Extracellular vesicles (EVs) represent a promising liquid biopsy platform in multiple myeloma (MM). We developed an MM EV Surface Protein Assay to quantify and dynamically monitor four MM EV subpopulations defined by targetable MM surface proteins (BCMA, CD38, GPRC5D, and CD319) across 336 serial blood samples from 45 relapsed/refractory MM (RRMM) patients treated with anti-BCMA chimeric antigen receptor (CAR) T-cell therapy. All four MM EV subpopulations significantly decreased in 43 patients with initial response, while BCMA+, GPRC5D+, and CD319+ MM EVs increased in 19 patients with progression, and antigen escape was detected by BCMA+ MM EVs. MM EV subpopulations differentiated minimal residual disease (MRD) status and complemented MRD for detecting early relapse before clinical progression. Notably, CD319+ MM EVs were early predictors of progression-free and overall survival in MRD-negative patients. This assay enables noninvasive monitoring of deep response, progression, and antigen escape, and stratifies survival in MRD-negative patients with RRMM.
PMID:41890853 | PMC:PMC13015583 | DOI:10.21203/rs.3.rs-8913641/v1
Environ Health (Wash). 2025 Nov 14;4(3):513-521. doi: 10.1021/envhealth.5c00401. eCollection 2026 Mar 20.
ABSTRACT
Prolonged exposure to fine particulate matter (PM2.5) has been linked to chronic liver injury and cancer. However, an alternative risk assessment method to prospective longitudinal studies of exposome-metabolome interactions for liver inflammation-associated hepatocellular carcinoma (HCC) is lacking. This study investigates the risk of long-term real-world PM2.5 exposure in hepatocarcinogenesis through machine learning techniques. Shotgun mass spectrometry (MS) imaging data were acquired from mouse models across a continuum of fibrosis, cirrhosis, and HCC for training a multiclass classification model to identify "No Risk", "Cancer Risk", and "Cancer". Direct infusion-MS data from PM2.5-exposed mouse livers were analyzed to classify risk. By integrating data-driven and knowledge-based approaches, 14 disease progression biomarkers were identified for modeling. Our results suggest that chronic real-world PM2.5 exposure can induce liver fibrosis, presenting cancer risk. Incorporating metabolomics, lipidomics, and transcriptomics, we propose PM2.5 exposure induces mitochondrial dysfunction, activates AMPK signaling, and increases ceramide accumulation, potentially mediating insulin resistance that contributes to nonalcoholic fatty liver disease and HCC progression. This work represents a significant advancement in assessing hepatotoxicity of environmental toxicants by reducing reliance on traditional animal testing methods. It also underscores the potential of emerging technologies in transforming our understanding of PM2.5 exposure, paving the way for targeted interventions.
PMID:41883379 | PMC:PMC13010293 | DOI:10.1021/envhealth.5c00401
Nature Medicine, Published online: 25 March 2026; doi:10.1038/s41591-026-04244-6
In a phase 1 trial, the in vivo generation of anti-BCMA CAR-T cells by lentiviral delivery was feasible and did not lead to dose-limiting toxicities in five patients with relapsed or refractory multiple myeloma.
Clin Mol Hepatol. 2026 Mar 11. doi: 10.3350/cmh.2025.1269. Online ahead of print.
ABSTRACT
BACKGROUND/AIMS: Lenvatinib resistance and immune exclusion limit outcomes in HCC. We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and PD-1 blockade.
METHODS: We established LS/LR HCC models and employed multi-omics (proteomics/RNA-seq), ChIP, luciferase, and RIP assays to map HKDC1 regulation. Tumor immunity was profiled by scRNA-seq, mIHC, and flow cytometry. SPD + lenvatinib efficacy was tested in cell lines, patient-derived organoids/xenografts. Tested therapy effect in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion; and analyzed a postoperative cohort (n = 40) treated with lenvatinib + PD-1.
RESULTS: HKDC1, upregulated in LR HCC, was transcriptionally activated by USF1 and promoted SMS-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or spermidine (SPD). SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib + aPD-1.
CONCLUSIONS: A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and support polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.
PMID:41812646 | DOI:10.3350/cmh.2025.1269
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