In-Press Preview
Abstract
Lung cancer histological subtypes include lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC). Although usually distinct, rare combined LUAD/SCLC tumors occur, and LUAD can transform into SCLC as a mechanism of resistance to targeted therapies, particularly in EGFR-Mutant LUADs with RB1/TP53 inactivation. Although PRC2 complex expression increases during this transformation, its functional role remains unclear. Using CRISPR-based autochthonous immunocompetent GEMMs, we found that inactivation of EED, the core PRC2 scaffolding subunit, impaired SCLC tumorigenesis and promoted LUAD histological identity likely through a NEUROD1-positive intermediate state. Mechanistically, EED loss derepressed bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes and NEUROD1. These same LUAD oncogenic signaling genes were bivalently repressed in human SCLC patient-derived xenografts, suggesting a conserved PRC2-dependent mechanism that represses LUAD oncogenic signaling and thereby supports the SCLC neuroendocrine identity. In a complementary EGFR-Mutant LUAD GEMM with Rb1 and Trp53 inactivation, EED inactivation at tumor initiation prevented the emergence of SCLC histology after EGFR oncogene withdrawal and redirected recurrent tumors toward mucinous LUAD states with reduced spontaneous metastasis. These findings identify PRC2/EED as a regulator of SCLC neuroendocrine identity and nominate pharmacologic EED inhibition for future investigation in therapy-associated LUAD-to-SCLC transformation.
Authors
Yixiang Li, Yasmin N. Laimon, Hyeonseo Cho, Marina Vivero, Gabriel Roberti de Oliveira, Maxwell D. Seager, Andrew Delcea, Varunika Savla, Yuting Chen, Yavuz T. Durmaz, Xintao Qiu, Shweta Kukreja, Rong Li, Talal El Zarif, Wesley Lu, McKayla Van Orden, Jacob E. Berchuck, Roderick T. Bronson, Shuqiang Li, Hongbin Ji, David A. Barbie, Katerina Politi, Matthew L. Freedman, Henry W. Long, Sabina Signoretti, Matthew G. Oser
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer-related mortality in men. Although poly(ADP-ribose) polymerase inhibitors (PARP inhibitor) are approved for mCRPC patients with homologous recombination repair (HRR) deficiencies, clinical trials combining Olaparib with PD-1/PD-L1 inhibitors have shown limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARP inhibitor in an unbiased manner, we performed bulk RNA sequencing on HRR-proficient MycCaP cells treated with the PARP inhibitor (Olaparib) versus vehicle control. Transcriptomics analysis revealed robust upregulation of CD73 (NT5E), an ectoenzyme and emerging immune checkpoint that generates extracellular adenosine, suggesting an adaptive mechanism that undermines Olaparib efficacy and promotes immunosuppression. CD73 induction by Olaparib was validated in both human and mouse prostate cancer cell lines, with more pronounced effects in HRR-compromised PTEN knockout (KO) cells. Mechanistically, olaparib-driven CD73 expression was mediated through DNA damage–activated ATR–CHEK1–IRF1 and TGF-β1–AKT signaling pathways. In parallel, Olaparib enhanced tumor immunogenicity by activating type I interferon (IFN) signaling and antigen presentation machinery. In vivo, combining olaparib with CD73 blockade significantly delayed tumor growth, improved T-cell infiltration, and augmented CD8⁺ T-cell effector function across HRR-proficient and PTEN KO prostate cancer models. These findings identify Olaparib-induced CD73 upregulation as an adaptive resistance mechanism and support Olaparib plus CD73 blockade as a promising therapeutic strategy for advanced prostate cancer, irrespective of HRR status.
Authors
Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang
Abstract
Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral anti-inflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In two glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing (snRNA-seq) and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell (iPSC)–derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.
Authors
Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J. Gill, Peter Canoll, Jeffrey N. Bruce
Abstract
Following acute kidney injury (AKI), a substantial subset of patients experiences an irreversible progression to chronic kidney disease (CKD), yet the molecular determinants governing this maladaptive transition remain elusive, and effective clinical interventions are lacking. Here, we identify lactate as a key metabolic determinant orchestrating the transition from AKI to CKD. Analysis of the UK Biobank cohort reveals that elevated circulating lactate independently predicts CKD development in AKI patients and correlates with fibrotic progression. Using murine ischemia-reperfusion injury models, we demonstrate that lactate drives sustained renal damage through post-translational lactylation of the RNA helicase DDX18. Mechanistically, p300-mediated lactylation of DDX18 at lysine 116 disrupts its nucleolar retention, causing redistribution to the nucleoplasm where it acquires enhanced binding affinity for CD44 mRNA. This subcellular relocalization stabilizes CD44 mRNA through altered RNA-protein interactions, thereby amplifying fibrotic signaling pathways. Therapeutically, we developed a kidney-targeted, cell-penetrating peptide that specifically inhibits DDX18 K116 lactylation, effectively attenuating fibrotic progression in injured kidneys. Our findings establish protein lactylation as a regulatory mechanism governing RNA helicase nucleolar localization and subsequent control of mRNA stability, revealing a potential therapeutic target for interrupting fibrotic processes in chronic kidney disease.
Authors
Lijun Dong, Jingwen Xie, Mengyuan Tao, Shuai Liu, Yueyang Lu, Tianxing Wu, Jian Geng, Qingyun Chen, Xiaoshan Zhao, Jianbo Zhao, Jia Zhou, Honghao Hou, Jun Ai, Tao Tao, Daming Zuo
Abstract
Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcriptomes and IR-related hormones of 75 breastfeeding women with healthy term infants during postpartum days 1-5. Participants were divided into IR tertiles based on plasma leptin-to-adiponectin ratio measurements. Those in the highest tertile had later SA onset with greater neonatal weight loss during postpartum days 1-5. Transcriptomic analysis on postpartum day 2 (n=4 high IR vs. n=8 low IR participants) showed transient suppression of mammary insulin and prolactin signaling genes, increased pro-inflammatory gene expression and altered expression of >200 mammary mitochondrial genes. These alterations were absent on postpartum days 3-5. Cultured mammary epithelial cells (MECs) treated with insulin showed upregulation of prolactin signaling and oxidative phosphorylation (OXPHOS) genes, with imaging and bioenergetic studies demonstrating that insulin promotes mitochondrial biogenesis and OXPHOS. Thus, our findings delineate roles for insulin in mammary bioenergetics and highlight mitochondrial dysfunction as a mechanism for delayed SA in insulin resistant women.
Authors
Xin Meng, Taha Elajnaf, Hussam Rostom, Michelle Ma, Annalee Furst, Bryony R. Davies, Isabella R. Honess, Gaurav Pandey, Isadora C. Furigo, Craig L. Doig, Jayne F. Martin Carli, Rajesh V. Thakker, Lars Bode, Kelsey E. Johnson, Fadil M. Hannan
Abstract
Authors
Diana B. Voss, Emily J. Shields, Andrey Poleshko, Li Li, Jun Li, Roger Wang, Mariacristina Calcagno, Rajan Jain, Cheryl L. Smith, Jonathan A. Epstein
Abstract
Immunotherapy resistance remains a challenge in immuno-oncology and predictive biomarkers are needed to guide combination immunotherapy selection for the individual patient. We show that elevated tumor-intrinsic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) signaling activity correlates with checkpoint inhibitor resistance in several independent cohorts of stage III/IV melanoma and gastroesophageal (GE) adenocarcinoma patients. In situ hybridization demonstrates that tumor NLRP3 copy-number gain is observed in immunotherapy resistant melanomas and GE adenocarcinomas harboring enhanced NLRP3 signaling activity. Nlrp3 amplification suppresses NOD-, LRR-, and CARD-containing 5 (NLRC5)-mediated MHC class I upregulation, while spatial transcriptomic analysis of patient-derived GE adenocarcinomas confirms that NLRP3 signaling activity inversely correlates with NLRC5 and major histocompatibility (MHC) class I-associated gene expression. Mechanistically, NLRP3 binds to and inhibits signal transducer and activator of transcription 1 (STAT1) dimerization, nuclear translocation, and NLRC5 transcription. Consistent with these findings, pharmacologic inhibition of the NLRP3 inflammasome augments tumor STAT1-NLRC5 signaling, enhances MHC class I surface expression, and overcomes anti-PD-1 resistance in an orthotopic model of gastric adenocarcinoma. This work reveals a fundamental link between cellular stress and tumor-mediated immune evasion and indicates that the tumor NLRP3 signaling pathway merits further clinical study as a therapeutic target and a source of companion biomarkers for overcoming checkpoint inhibitor resistance in cancer patients.
Authors
Balamayroon Theivanthiran, Nagendra Yarla, Kaylee Villarreal, Y-Van Nguyen, Mahere Rezazade Bazaz, Ernesto Pena Calderin, Linda Cao, Kyra Majors, Michael P. Plebanek, Alisha Holtzhausen, Emily Bolch, Douglas B. Johnson, Hope Uronis, John H. Strickler, Nicholas C. DeVito, Brent A. Hanks
Abstract
Liver sinusoidal endothelial cells (LSECs) regulate nutrient flux and immune surveillance within the hepatic niche, yet how they function as metabolic stress sensors that instruct adaptive immune remodeling during metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Here, single-nucleus transcriptomics of human MASLD reveals stage-dependent activation of the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling in LSEC comparable to that in macrophage, with endothelial activation showing greater responsiveness to metabolic stress. Endothelial-specific STING deletion attenuates steatohepatitis and fibrosis in mice. Mechanistically, LSEC-intrinsic STING activation reprograms the angiocrine landscape through NF-κB-mediated transcriptional repression of the endothelial-derived factor BMP4. Loss of BMP4 disrupts the tolerance-supporting sinusoidal immunometabolic niche, skewing CD4⁺ T cell differentiation toward pathogenic Th17 states while destabilizing Treg, collectively exacerbating hepatic metabolic failure. In human MASLD, endothelial STING activity inversely correlates with BMP4 expression at single-cell resolution. Targeted delivery of a STING inhibitor to LSECs using peptide-functionalized nanoparticles restores hepatic metabolic-immune balance at one-tenth the systemic dose. Together, these findings establish endothelial STING as a metabolically responsive vascular immune checkpoint that links chronic metabolic stress to adaptive immune remodeling and fibrotic progression.
Authors
Zhi-Bin Lin, Peng Zou, Xian-Yi Ma, Jun-Bo Song, Hong Zhang, Wei Du, Dan Wei, Ping Song, Xin Hong, Jingjing Liu, Zhi-Qiang Fang, Hao Xu, Fei He, Juan-Li Duan, Ke-Feng Dou, Lin Wang
Abstract
Transfer RNA (tRNA) modifications play a critical role in regulating codon-specific mRNA translation and enabling tumor cell adaptation. The RNA methyltransferase METTL1 installs N7-methylguanosine (m⁷G) modifications on tRNAs, thereby shaping codon usage and translational output. However, the function and mechanistic contribution of the METTL1–tRNA axis in pancreatic ductal adenocarcinoma (PDAC) remain poorly defined. Here, we show that METTL1 is overexpressed in PDAC tissues and that elevated METTL1 expression is associated with poor patient survival. Genetic ablation of METTL1 markedly suppresses PDAC cell proliferation, migration, and tumor growth in vitro and in vivo. Mechanistically, METTL1 loss selectively reduces m⁷G-modified valine tRNAs – particularly, Val-AAC, Val-CAC, and Val-TAC – leading to impaired translation of valine-enriched oxidative phosphorylation transcripts. As a consequence, METTL1 deficiency disrupts mitochondrial respiration and energy production in PDAC cells. Consistent with this model, valine tRNA levels are elevated in PDAC tissues, and their selective depletion phenocopies METTL1 loss by impairing mitochondrial bioenergetics and tumor cell fitness. Thus, the METTL1–valine tRNA axis promotes PDAC progression through codon-dependent translational control of mitochondrial electron transport chain and oxidative metabolism. Together, our findings identify a METTL1–tRNA–mitochondrial signaling axis as a previously unrecognized metabolic vulnerability and a promising therapeutic target in pancreatic cancer.
Authors
Jiabei Zhu, Qi Zhang, Douglas Evans, Rui Su, Qiuhui Pan, Ajay Goel
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global health concern. Nevertheless, its underlying pathological mechanisms remain poorly understood. Here, we showed that E3 ubiquitin ligase ring finger protein 10 (RNF10) protein levels were positively correlated with MASLD in both mice and humans. Hepatic-specific Rnf10 deletion attenuated liver steatosis, inflammation, and fibrosis. Conversely, adeno-associated virus (AAV)-mediated hepatic-specific Rnf10 overexpression exacerbated MASLD-related phenotypes. Mechanistically, RNF10 interacted with carnitine palmitoyltransferase 1A (CPT1A) and facilitated its degradation through K48-linked ubiquitination, thereby inhibiting fatty acid oxidation, promoting hepatic lipid accumulation, and ultimately exacerbating liver inflammation and fibrosis. Moreover, we utilized triantennary N-acetylgalactosamine (GalNAc) to deliver small interfering RNA (siRNA) specifically targeting Rnf10 to hepatocytes. This approach effectively ameliorated diet-induced liver steatosis, inflammation, and fibrosis in mice. Therefore, interfering with the expression or function of RNF10 may be a promising therapeutic strategy for MASLD.
Authors
Chunyuan Du, Yinliang Zhang, Hongkai Chang, Chaofan Xu, Sufang Sheng, Ke Xu, Wei Qiao, Yanjun Liu, Tongtong Zhang, Yong Gao, Peng Li, Yongsheng Chang
No posts were found with this tag.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)