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Abstract
GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and mediate the physiological control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem Glp1r neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Here, we silenced Glp1r neurons in the nucleus of the solitary tract or area postrema (NTSGlp1r or APGlp1r neurons, respectively) or restored their GLP1R signaling on an otherwise GLP1R-deficient background to determine physiological and pharmacological roles for each neuron population. Although NTSGlp1r neurons contributed to the normal restraint of food intake and body weight, they failed to mediate GLP1RA-dependent weight loss. In contrast, while we detected no role for APGlp1r neurons in physiological feeding, they mediated both the weight-lowering and aversive effects of GLP1RAs. Therefore, while non-aversive NTSGlp1r neurons control physiologic satiation they do not contribute to weight loss during GLP1RA treatment. Rather, APGlp1r neurons mediate both the weight-lowering and aversive effects of GLP1RAs, preventing the separation of their nauseating and weight-loss effects at a circuit level.
Authors
Warren T. Yacawych, Yi Wang, Guoxiang Zhou, Shad Hassan, Cagri Bodur, Elisabeth Walters, John G. Santinga, Frederike Sass, Martin deVaux, Stace Kernodle, Iris Wu, Jenny M. Brown, Dylan M. Belmont-Rausch, Alan C. Rupp, Abigail J. Tomlinson, Zitian Lin, Emma VanTongeren, Anna Secher, Kirsten Raun, Tune H. Pers, Randy J. Seeley, Martin G. Myers Jr., Weiwei Qiu
Abstract
Obesity-associated inflammation impairs pancreatic β-cell function, yet the mechanisms by which immune cells acutely regulate insulin secretion remain poorly defined. Here, we identify myeloid Gq signaling as an immunometabolic node linking macrophage lipid sensing to impaired insulin secretion. Using chemogenetic DREADD-mediated activation of myeloid Gq, we show that acute macrophage Gq activation impairs glucose-stimulated insulin secretion (GSIS) in vivo, whereas myeloid Gαq ablation enhances GSIS. Mechanistically, Gq activation rapidly induced AMPK phosphorylation and sphingolipid remodeling independently of canonical inflammatory cytokines. Macrophage-derived sphingolipids impaired β-cell insulin signaling and GSIS through CD36-PKCζ, while inhibition of CD36, AMPK, or sphingolipid metabolism restored β-cell function. We further identified GPR18, a Gq-coupled endocannabinoid-responsive GPCR, as an upstream regulator. GPR18 activation with N-arachidonoyl glycine (NAGly) recapitulated this phenotype, whereas myeloid Gαq deletion or Gpr18/AMPK silencing abolished it. GPR18 signaling predominantly engaged Gq rather than Gi pathways. In human tissues, GPR18 was enriched in islet macrophages, and NAGly suppressed GSIS in primary human islets. Thus, a conserved macrophage GPR18-Gαq-AMPK-sphingolipid axis dynamically regulates β-cell function and represents a potential therapeutic target in obesity and type 2 diabetes.
Authors
Simran Singh, Ashish Kumar, Sudipta Paul, Mriganka Sarkar, Santhosh Duraisamy, Ganesh Timalsina, Raashidha Farhath, Harender Yadav, Seema Kuldeep, Soumita Bhaumik, Kunj Kumar Prajapati, Saahiba Thaleshwari, Anuj Gargya, Tamojit Santra, Sonal Amit, Rashmi Parihar, Santosh K. Misra, Hamim Zafar, Luiz F. Barella, Michael A. Kalwat, Dharmaraja Allimuthu, Sai Prasad Pydi
Abstract
Successful implantation requires precise coordination of uterine epithelial receptivity, stromal decidualization, and immune homeostasis during a narrow peri-implantation window. Although retinoic acid (RA) signaling has been implicated in female reproduction, the endogenous and isoform-specific roles of retinoic acid receptors (RARs) remain poorly defined. Here, we combined isoform-specific genetic mouse models, transcriptomic profiling, and functional studies in mouse and human stromal cells to determine how RAR signaling regulates early pregnancy. We found that RARG is the dominant RAR isoform required for female fertility in mice, as its deletion severely impaired implantation, whereas combined loss of all RAR isoforms caused complete reproductive failure. RAR deficiency disrupted multiple sequential reproductive processes, including sperm transport and fertilization, suppression of uterine estrogen receptor activity, acquisition of stromal decidualization competence, and maintenance of uterine immune homeostasis. Transcriptomic analyses identified conserved epithelial and mesenchymal programs altered across independent RAR-deficient mouse models and revealed significant overlap with endometrial gene signatures from women with recurrent implantation failure. In human endometrial stromal cells, suppression of the RARA isoform consistently disrupted decidualization across three independent primary cell lines and an immortalized cell model. Together, these findings identify RAR signaling as a critical regulator of early pregnancy and reveal conserved, isoform-specific functions required for early pregnancy.
Authors
Yan Yin, Emily Y. So, Eliana Wolf, Vivian Robles Pinos, Meade Haller, Renjie Shang, Sylvia C. Hewitt, Alex Tak, Brent M. Bany, David Y. Chen, Mengcheng Shen, Francesco J. DeMayo, Liang Ma
Abstract
Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.
Authors
Phan Q. Duy, Benjamin C. Reeves, Huanxing Sun, Xueyan Peng, Pazhanichamy Kalailingam, Garrett Allington, Evan Dennis, Le Thi Hao, Lei Wang, David Rufino-Ramos, Shujuan Zhao, Qiang Li, Neel H. Mehta, William C. Davalan, Mason Blacker, Anthony J. Piscopo, Shozeb Haider, Baojian Fan, Kedous Y. Mekbib, Shuai Shao, Carol Nelson-Williams, TuKiet T. Lam, Benjamin P. Kleinstiver, Patricia L. Musolino, Seth L. Alper, Sheng Chih Jin, Erica L. Herzog, Kristopher T. Kahle
Abstract
Membranous nephropathy (MN) is an autoimmune kidney disease and a major cause of nephrotic syndrome in adults. Although autoantibodies against phospholipase A2 receptor 1 (PLA2R) and complement activation are central to disease pathogenesis, the mechanisms by which anti-PLA2R antibodies activate complement at the podocyte surface remain incompletely defined. Here, we cloned 14 patient-derived anti-PLA2R monoclonal antibodies (mAbs) and found that they predominantly recognized the N-terminal cysteine-rich (CysR) and C-type lectin domain 1 (CTLD1) regions of PLA2R. Individual anti-PLA2R mAbs induced little or no complement-dependent cytotoxicity (CDC) of PLA2R-expressing podocytes in vitro. In contrast, paired mAbs targeting distinct epitopes, particularly CysR and CTLD1, markedly enhanced CDC. This effect was strongest for IgG1 and IgG3 antibodies, whereas IgG4 alone did not activate complement but modulated CDC in combination with IgG1. Purified IgG from patients with PLA2R-associated MN similarly induced CDC, which was augmented by addition of anti-PLA2R IgG1 and reduced by anti-PLA2R IgG4 or Fab fragments targeting CysR or CTLD1. In human PLA2R-expressing mice, paired anti-PLA2R antibodies increased glomerular complement deposition and induced albuminuria. These findings identify epitope pairing as a key determinant of complement activation in PLA2R-associated MN and support epitope-specific targeting strategies as a promising avenue for therapeutic intervention.
Authors
Tsai-Yi Wu, Kun-Hua Tu, Larissa Seifert, Kung-Wei Lin, Han-Po Shih, Yu-Fang Lo, Jhan-Jie Peng, Gunther Zahner, Oliver Kretz, You-Ning Lin, Chen-Xuan Kang, Jing-Ya Ding, Yi-Ran Tu, Li-Yi Ma, Ya-Ting Chuang, Chia-Chi Lo, Yu-Huan Tsai, Chih-Wei Yang, Nicola M. Tomas, Cheng-Lung Ku
Abstract
Pain is a common and disabling feature of myotonic disorders, yet its biological basis remains poorly understood and no targeted analgesic therapies currently exist. Here, we demonstrate that skeletal muscle hyperexcitability is sufficient to initiate a persistent pain state independent of inflammation, nerve injury, or overt tissue damage. Using complementary pharmacological and genetic models of myotonia resulting from loss of the voltage-gated skeletal muscle chloride channel ClC-1 function, we show that transient and chronic myotonia produce robust mechanical, thermal, and cold hypersensitivity, as well as spontaneous pain-like behavior. Notably, pain-like behaviors induced by transient myotonia persist long after overt motor symptoms have resolved, suggesting that a transient episode of muscle hyperexcitability is sufficient to trigger prolonged alterations in nociceptive processing. Physiological recordings revealed altered excitability of dorsal root ganglion and superficial dorsal horn neurons and enhanced sensory-evoked activity in the parabrachial nucleus, indicating altered nociceptive processing across multiple levels of the pain neuraxis. Transient myotonia increased total sodium current density in sensory neurons, with a shift toward a greater tetrodotoxin-resistant current fraction. Pharmacological inhibition with the NaV1.8-directed analgesic Suzetrigine markedly attenuated pain-like behaviors in both models of myotonia. Together, these findings establish a link between myotonia and persistent alterations in nociceptive processing and identify NaV1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.
Authors
Tyler S. Nelson, Aida Calderon-Rivera, Heather N. Allen, Alaina L Waters, Emanuel Loeza-Alcocer, Jorge B. Pineda-Farias, Narges Pachenari, Santiago Loya-Lopez, Kimberly Gomez, Erick J. Rodriguez-Palma, Paz Duran, Michael S. Gold, Rajesh Khanna
Abstract
Transport of nucleoside chemotherapeutic drugs into tumor cells is primarily accomplished through Equilibrative Nucleoside Transporter 1 (ENT1), considered to be constitutively-active, redistributing drugs across lipid bilayers via facilitated diffusion. Here we discover that ENT1 is not constitutively-active but rather requires activation of acid sphingomyelinase (ASMase) by gemcitabine, generating ceramide-rich platforms (CRPs) on external plasma membranes of endothelial and tumor cells into which ENT1 inserts, dimerizing therein to functionalize transmembrane gemcitabine transport. Whereas sarcoma cells synthesize minimal ASMase, they take up gemcitabine poorly in vitro and in murine xenografts. A strategy designed to augment gemcitabine-induced ASMase secretion into the extravascular space by ASMase-rich neo-angiogenic cells, which then targets tumor cell plasma membranes, yields “bystander” CRPs on sarcoma cells and ENT1 insertion therein, conferring markedly-enhanced gemcitabine uptake and xenograft response. Engaging this biology in a prospective Phase II clinical trial in advanced sarcoma yielded robust volumetric changes in evaluated tumors that developed early and were often durable.
Authors
Aditya Ganju, Shyam Rao, Mark A. Dickson, Robert A. Lefkowitz, Chris Thompson, Jin Cheng, Katia Manova, Adriana Haimovitz-Friedman, Gary Schwartz, Zhigang Zhang, Zvi Fuks, William D. Tap, Richard Kolesnick
Abstract
Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum–mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
Authors
David R. Eberhardt, Emma C. Rekate, Yasmin B. Masini, Hannah E. Duron, David Mollinedo, Adrian M. Velarde, Devorah Stucki, Tara R. Price, Sandra H.J. Lee, Enrique Balderas, Neeraj K. Rai, Ashley R. Bratt, Anthony M. Balynas, Chris J. Stubben, Ryan Bia, Sudipa Maity, Nicolas Hartel, Xue Yin, Andrea Corbin, Anshu Kumari, Dung M. Nguyen, Daisuke Shimura, Vu D. Nguyen, Vishaka Vinod, Kamrul H. Chowdhury, Francisco Verdeguer, Joel Zvick, Patrice N. Mimche, Sihem Boudina, Stavros G. Drakos, Ademuyiwa S. Aromolaran, Sarah Franklin, Vivek Garg, Robin M. Shaw, William L. Holland, Scott A. Summers, Marcus G. Pezzolesi, Jared Rutter, Kimberley J. Evason, Dipayan Chaudhuri
Abstract
Multiple sclerosis (MS) is a complex inflammatory disease of the CNS resulting from an intricate interplay between genetic predisposition and environmental factors. Vitamin D (VD) deficiency is one of the established risk factors for MS. CD46 costimulation of CD4+ T cells induces a switch from Th1 to type I regulatory cells (Tr1), characterized by increased IL-10 production. This switch is impaired in MS T cells but can be restored by VD, which also strongly promotes expression of CD226 on CD46-activated T cells. The rs763361 polymorphism in the CD226 gene, resulting in a non-synonymous Gly307Ser variant, is associated with increased risk for MS. Herein, we show that expression of this CD226 risk allele disrupts the ability of CD46-activated T cells to operate the IFNγ/IL-10 switch upon VD exposure. Mechanistically, the risk variant impairs activation of the integrin LFA-1, which promotes the Tr1 phenotype. LFA-1-mediated Tr1 differentiation is also impaired in MS T cells expressing the CD226 risk allele upon CD46 and VD stimulation. Our study unveils how, in the context of MS susceptibility, a genetic polymorphism and an environmental factor act in concert to control the differentiation of Tr1 cells.
Authors
Saniya Kari, Aymeline Debonlier, Thibault Angles, Beatriz Chaves, Charles Grosjean, Florence Bucciarelli, Valérie Duplan-Eche, Lucie Nozeran, Jessica Lavery, Elena Morandi, Beatrice Pignolet, Max Mimpen, Joost Smolders, Roland Liblau, Abdelhadi Saoudi, Jan Damoiseaux, Frederick Masson, Loïc Dupré, Anne L. Astier
Abstract
Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive aggressive acute myeloid leukemia (AML) and confer poor prognosis. Although FLT3 inhibitors have improved outcomes, their efficacy is frequently limited by microenvironment-mediated signaling and treatment-emergent resistance. XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for multiple solid tumors. Biochemical, multi-omics, and functional analyses showed that XY0206 directly engages FLT3 and suppresses downstream STAT5, AKT, and ERK signaling, resulting in apoptosis in FLT3-ITD AML cells. Across models of FLT3-dependent resistance, XY0206 retained antileukemic activity, including in FLT3-ITD cells harboring the F691L gatekeeper mutation, a recurrent alteration conferring resistance to approved FLT3 inhibitors. In primary AML blasts and xenograft models, XY0206 exhibited enhanced antileukemic activity with favorable tolerability relative to gilteritinib. In a phase I/II trial (NCT04471064) of XY0206 monotherapy in patients with relapsed or refractory (R/R) AML, XY0206 achieved a composite complete remission rate (CRc) of 45.7% overall, with a notable 60.0% CRc rate among patients with FLT3-ITD mutations. Three of eight patients with prior FLT3 inhibitor-exposed R/R AML also achieved CRc. Together, these findings support further clinical evaluation of XY0206 as a FLT3-directed therapeutic in AML, particularly in disease settings with reduced sensitivity to existing FLT3 inhibitors.
Authors
Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (PanNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program, and a secretory neuroendocrine program. Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in PanNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that neuronal-like-high regions localized to densely cellular tumor areas with relative depletion of stromal infiltration, whereas secretory neuroendocrine-high regions occupied fibrovascular and stromal niches enriched for endothelial, fibroblast, and myeloid populations, and associated with TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enriched for pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.
Authors
Julie Karam, Samantha E. Hoffman, Amanda Garza, Dan Gui, Hannah I. Hoffman, Breanna M. Titchen, Yutaro Tanaka, Erica Pimenta, Theodora Pappa, Laura Valderrabano, Kevin Bi, Riaz Gillani, Lauren Brais, Erin Shannon, Jason L. Hornick, Jihye Park, Jennifer Chan, Eliezer M. Van Allen
Abstract
Regulatory T (Treg) cells hold great promise as next-generation therapeutics for autoimmune diseases. However, maintaining their functional persistence within inflamed tissues remains a major translational challenge. Using an in vitro system that recapitulates the inflammatory CNS milieu of multiple sclerosis (MS), together with a pooled shRNA screen, we identify necroptotic signaling as a key driver of Treg cell death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Treg cells in both a mouse model of MS and patients with MS exhibit a preferential susceptibility to RIPK1 kinase-dependent necroptosis. Mechanistically, a FOXP3-driven low-glucose metabolic program renders Treg cells intrinsically susceptible to necroptosis by limiting O-GlcNAc modification on RIPK1. This vulnerability is not shared by conventional T cells under comparable inflammatory conditions. Finally, in combined with adoptive Treg cell transfer, we show that selective inhibition of necroptosis in Treg cells enhances their survival and suppressive function at sites of active inflammation, thereby reducing autoimmune pathology in mouse models of MS and systemic lupus erythematosus. Together, these findings identify necroptotic cell death as a barrier to Treg persistence within inflamed tissues and highlight the therapeutic potential of necroptosis-resistant Treg cells for the treatment of autoimmune diseases.
Authors
Qiaoyan Wu, Na Cui, Li Gao, Zhihui Lu, Xiang Ao, Rui Pang, Xingyan Li, Heling Pan, Daichao Xu, Peiying Li, Junying Yuan, Chengyu Zou
Abstract
The neutrophil-to-lymphocyte ratio (NLR) is associated with unfavorable prognosis and hemorrhagic transformation (HT) in patients with ischemic stroke, yet the underlying mechanisms remain unclear. Using patient samples and a murine stroke model, we identified CD8⁺ regulatory T cells (CD8 Tregs) key regulators of neutrophil homeostasis after ischemic stroke, thereby limiting endothelial disruption and HT. Loss of CD8 Tregs expanded circulating neutrophils by extending their lifespan rather than altering proliferation, bone marrow release, or direct cytotoxicity. Mechanistically, CD8 Tregs shortened neutrophil lifespan by modulating HIF-1α–dependent glycolytic activity and relieving PD-L1–mediated suppression of bone marrow clearance. Finally, co-culture experiments with human CD8 Tregs and neutrophils revealed similar neutrophil-regulatory effects, accompanied by improved endothelial barrier integrity. These findings reveal a previously unrecognized CD8 Treg–neutrophil axis and suggest potential therapeutic strategies for preventing HT after stroke.
Authors
Jianan Lu, Qia Zhang, Jiarui Chen, Huaming Li, An Ping, Ziyang Jin, Xiaotao Zhang, Yichen Gu, Xuejiao Dai, Zihong Chen, Yajun Qian, Guoqiang Zhang, Jun Yu, Jianmin Zhang, Ligen Shi
Abstract
Authors
Chenjian Gu, Yili Fang, Yixuan Wang, Eric Tycksen, Gayathri Kondepati, Chuang Li, Kendrah O. Kidd, Jun Liu, Fumihiko Urano, Maria Lindahl, Anthony J. Bleyer, Srikanth Singamaneni, Zhao Sun, Ying Maggie Chen
Abstract
Background: Combined checkpoint blockade (CCB) of programmed-death-1 (PD-1) and cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4) is highly active in melanoma but limited by significant morbidity from immune-related adverse events (irAEs). Effective strategies to prevent CCB-mediated irAEs are lacking. Methods: Patients with advanced melanoma were randomly assigned to receive standard of care ipilimumab and nivolumab alone (Arm-A: ipi/nivo, n=7) or with one cycle of rituximab (Arm-B; ipi/nivo+rituximab, n=7). Results: Patients receiving ipi/nivo+rituximab experienced lower rates of > grade-3(G3) irAEs (14% versus 57%) and superior G3-irAE-free survival compared to those in ipi/nivo arm (2-year G3-irAE-free survival 86% versus 29% (p=0.01), without adverse impact on tumor regression or survival. G3 hypersensitivity reactions to rituximab (43% in Arm-B) prompted trial closure. Rituximab depleted pre-therapy activated naïve B cells linked to autoimmunity and enhanced CCB-mediated induction of myeloid inflammation and CXCL13+ICOS+ CD4 T cells. Conclusion: B-cell depletion favorably modulates CCB-mediated immune activation and may reduce irAE risk. Trial Registration: ClinicalTrials.gov NCT03719131 Funding: NIH
Authors
Kavita M. Dhodapkar, Antonio Matera, Alyssa M. Duffy, Azmain Taz, Renee Julia Manalo, Melinda Yushak, Ragini Kuchadkar, David H. Lawson, Madhav V. Dhodapkar
Abstract
Authors
Vlad Moisoiu, Roxanne Lourman, Frank Szulzewsky, Tobias Kessler, Giulio Collotta, Antonio Porro, Anne Bertolini, Franziska Singer, Patrick J. Cimino, Caroline Hertler, Wolfgang Wick, Guido Reifenberger, Eric C. Holland, Alessandro A. Sartori, Michael Weller, Hans-Georg Wirsching
Abstract
Authors
Diwakar Turaga, Chang-Ru Tsai, Yuka Morikawa, Hanna J. Tadros, Yi Zhao, Lalita Wadhwa, Iki Adachi, Xiao Li, James F. Martin
Abstract
Triple-negative breast cancer (TNBC), characterized by aggressive behavior and poor prognosis, presents a formidable clinical challenge. Despite guideline endorsement of chemoimmunotherapy as a standard treatment in TNBC, durable responses remain rare, largely due to an immunologically “cold” tumor microenvironment (TME). Through integrated analysis, we identified the F-box protein FBXW5 as a tumor-intrinsic immunosuppressive regulator, whose expression is elevated in immunologically “cold” TNBC and correlates with dismal patient survival. Genetic knockdown of murine Fbxw5 suppressed tumor growth, reinvigorated CD8+ T cell-mediated antitumor immunity, and sensitized TNBC tumors to both single-agent and combined chemo-immune therapy in preclinical models. Mechanistically, FBXW5 acts within the SKP1/CUL1/F-box protein (SCF) E3 ligase complex to bind RIGI and MDA5, promoting their K27-linked polyubiquitination and subsequent SQSTM1-mediated autophagic degradation. This process blunts cytosolic RNA sensing and type I interferon (IFN-I) signaling, thereby limiting CD8+ T cell infiltration and activation. Our findings establish FBXW5 as a master regulator of the “cold” TME, presenting a potential predictive biomarker and actionable therapeutic target for enhancing chemoimmunotherapy in TNBC.
Authors
Xin Li, Tong Chen, Wenjing Zhao, Jiaxing Li, Yifan Shang, Bing Chen, Lijuan Wang, Ning Zhang, Xiaoli Kong, Yiran Liang, Yaming Li, Chen Li, Dianwen Han, Xi Chen, Shan Jiang, Chao Yang, Dan Luo, Tingting Ma, Qifeng Yang
Abstract
Mutations in the survival of motor neuron 1 (SMN1) can reduce functional SMN protein levels, which causes Spinal Muscular Atrophy (SMA), a disease affecting the nervous system and peripheral tissues, including the immune system. Yet, SMN expression across immune cell subsets and the impact of SMN-modulating therapies on the immune system remains underexplored. We found that in neonatal mouse spleen, SMN expression was highest in B cells, which were massively reduced in SMA mice. In human PBMCs from adults, DCs and monocytes expressed the highest SMN levels, whereas SMA patients showed reduced DC and increased B cell frequencies. Patients receiving systemic versus CNS-restricted therapy showed similar differences in immune cell composition and SMN levels. Similarly, an exploratory cohort including untreated patients did not indicate a substantial treatment-specific effect relative to controls. To assess the impact of differentiation on SMN, PMA-treated THP-1 cells were analyzed, revealing enhanced aberrant SMN splicing and increased SMN-positive Cajal bodies. In conclusion, SMN levels vary across immune cell types, and reduced SMN levels are associated with altered immune cell composition. Immune alterations and decreased SMN levels were observed in both treated and untreated SMA patients and may contribute to dysfunctions of the immune system in SMA.
Authors
Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus
Abstract
Cancer hotspot mutations of unknown function often obscure the functional understanding of the molecular pathways underlying cancer formation and limit precision medicine progress. Here, we investigated unresolved driver functions of RHOA in head and neck squamous cell carcinoma (HNSCC). Our investigation reveals that RHOA E40Q is a partial loss-of-function allele which paradoxically promotes tumorigenesis only in the absence of wild-type RhoA. Therefore, mice expressing RHOA E40Q specifically in keratinocytes lacking wild-type RhoA spontaneously developed squamous cell carcinoma and showed defective hair shaft formation. Mechanistically, this is related to increased replication stress and genome instability caused by aberrant expression of cell cycle regulators and DNA repair genes, independent of the classical RhoA effectors ROCK and DIAPH. These data establish RHOA E40Q as an unusual, context-dependent oncogenic driver: a seemingly inactive variant that unleashes its tumor-promoting potential only when the wild-type allele is absent.
Authors
Justine Noujarède, Qiuyue Wang, Eleftherios Panagiotis Kokkinogenis, Yuewan Luo, Ivona Cudina, Simon Willaume, Clémence Mooser, Lap Phuoc Nguyen, Mads Frederik Poulsen, Simon Heijmerikx, Thu Han Le Phan, Xiubin He, Jesper Bøje Andersen, Claus Storgaard Sørensen, Cord Brakebusch
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ISSN: 0021-9738 (print), 1558-8238 (online)