Huang AY, Zhou Z, Talukdar M
… +32 more, Enyenihi L, Miller MB, Chhouk B, Rosen I, Zheng M, Zhou M, Yang A, Stronge E, Durens M, Nguyen M, Choi J, Zhao B, Khoshkhoo S, Kim J, Andersen R, An Z, Cheng Y, Ganz J, Mekerishvili L, Travaglini KJ, Gabitto MI, Hodge RD, Kaplan ES, Belk JA, Landau D, Lein ES, De Jager PL, Bennett DA, Marro SG, Papapetrou EP, Lee EA, Walsh CA
Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide varia...Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood, suggesting a likely hematopoietic origin. Single-nucleus RNA sequencing data from 62 additional AD and control brains revealed increased somatic copy number variants (sCNVs) associated with CH in AD MLBMs, whereas single-cell multi-omic analyses demonstrated that sSNV- and sCNV-carrying MLBMs exhibited inflammatory and proliferative transcriptional signatures characteristic of disease-associated microglia. These signatures were recapitulated in induced pluripotent stem cell-derived microglia-like cells with TET2, ASXL1, and DNMT3A variants. These findings suggest that clonal somatic driver variants in MLBMs are enriched in AD, potentially promoting neuroinflammation and neurodegeneration.
With the ongoing rise in global temperatures, the prevalence of heat-stress-related chronic health disorders has increased. However, whether heat stress has an enduring impact on metabolic health remains unclear. Here, w...With the ongoing rise in global temperatures, the prevalence of heat-stress-related chronic health disorders has increased. However, whether heat stress has an enduring impact on metabolic health remains unclear. Here, we report that mice exposed to heat stress were more susceptible to metabolic dysfunction upon subsequent exposure to an obesogenic diet. Upon heat stress, we found that elevated skin-derived kallikrein-related peptidase 14 (KLK14) imprinted hypothalamic LRRC7 astrocytes. These astrocytes further suppressed neighboring paraventricular nucleus (PVN) neuron activity via alkB homolog 1, histone H2A dioxygenase (ALKBH1)-mediated epigenetic modification of γ-aminobutyric acid (GABA) synthesis, thus driving visceral fat deposition in a sympathetic nervous-system-dependent manner. Heat stress exposure also increased susceptibility to metabolic dysfunction in human subjects, with vitamin A treatment limiting the production of KLK14 and ameliorating metabolic disturbances in humans and mice. Together, our findings reveal a skin-hypothalamus axis linking heat memory and metabolic dysfunction and highlight that global warming is exacerbating metabolic diseases.
Rathore U, Dugan E, Thornton H
… +35 more, Kumar VE, Dajani R, Burdick RC, Young JM, Steinhart Z, Lao R, Delviks-Frankenberry KA, Choi W, Henriques WS, Echeverria I, Dann E, Dureja I, Pathak N, Arce MM, McKetney J, Umhoefer JM, Parulekar S, Schmidt R, Polacco BJ, Neidleman J, Montano M, Nguyen VQ, Sali A, Levy JA, Tenthorey JL, Cheng Y, Roan NR, Swaney DL, Kaake RM, Dodgson SE, Hiatt J, Pathak VK, Malik HS, Krogan NJ, Marson A
Host factors that promote or restrict human immunodeficiency virus (HIV) infection in human CD4+ T cells have not been comprehensively identified. We employed orthogonal genome-wide CRISPR activation (CRISPRa) and CRISPR...Host factors that promote or restrict human immunodeficiency virus (HIV) infection in human CD4+ T cells have not been comprehensively identified. We employed orthogonal genome-wide CRISPR activation (CRISPRa) and CRISPR knockout screens in primary CD4+ T cells to discover pro- and anti-HIV host factors systematically. Secondary pooled screens and individual perturbations validated high-confidence hits and revealed diverse mechanisms of action. CRISPRa uncovered multiple potent antiviral factors, including PI16, PPID, SHISA3, and ITM2A. PI16 interacts with host factors involved in HIV fusion and inhibits viral entry, whereas PPID (Cyp40), a paralog of the proviral cyclophilin CypA, binds capsid and reduces nuclear import of the HIV core. Structural modeling, evolutionary analyses, and targeted mutagenesis revealed domains and residues required for PPID-mediated HIV restriction, including non-human primate ortholog substitutions that enhance antiviral activity. Together, these data define the functional HIV-host interaction landscape in primary human T cells and uncover new mechanisms modulating infection.
Cell fate manipulation is powerful for generating desired cell types through reprogramming. However, reprogramming induces dramatic changes in cell states and identities, which can be risky, necessitating strict regulati...Cell fate manipulation is powerful for generating desired cell types through reprogramming. However, reprogramming induces dramatic changes in cell states and identities, which can be risky, necessitating strict regulation to ensure safety and efficiency. p53 is essential for genome stability; however, it functionally opposes oncogenes comprising the Yamanaka factors. Delicately balancing p53 activity for efficient reprogramming has proven challenging. Here, we demonstrate that p53 is essential for chemical reprogramming, unlike its inhibitory role in transcription factor-mediated reprogramming. Unexpectedly, suppressing p53 impairs the generation of chemically induced pluripotent stem cells (CiPSCs). p53 prevents excessive epithelial-to-mesenchymal transition during the early reprogramming stages. Retinoic acid signaling activation promotes CiPSC generation by leveraging p53's anti-metastatic function via BTG2. Cell proliferation ability is sustained in the presence of p53 expression by regulating p21 with chemicals. p53 preservation shows practical advantages in securing genome integrity; thus, chemical reprogramming is promising for delicately balancing p53 activity and achieving efficient reprogramming for cell fate manipulation.
One means of controlling insect disease vectors and pests is with compounds that manipulate their behavior. An extraordinary variety of phytochemicals, i.e., compounds produced by plants, activate insect chemosensory sys...One means of controlling insect disease vectors and pests is with compounds that manipulate their behavior. An extraordinary variety of phytochemicals, i.e., compounds produced by plants, activate insect chemosensory systems. Fruits and vegetables present a source of compounds that are inexpensive and safe. A "phytoscreen" of 43 fruits and vegetables identified garlic as a potent deterrent of mating and egg laying in Drosophila. Diallyl disulfide, a garlic compound, deters both behaviors. Mating and egg-laying effects depend on taste and the TrpA1 channel. Garlic inhibits mating and egg laying in Aedes vector mosquitoes and mating of the tsetse fly Glossina morsitans. Garlic exposure increases expression of Drosophila head genes, including female-specific independent of transformer (fit), which encodes a satiety hormone that is essential for the effect of garlic on egg-laying preference.
Patients with resected, high-risk melanoma receive adjuvant immune checkpoint blockade (ICB), yet clinical benefit remains unpredictable, with 25%-40% of patients experiencing recurrence. To evaluate whether pre-treatmen...Patients with resected, high-risk melanoma receive adjuvant immune checkpoint blockade (ICB), yet clinical benefit remains unpredictable, with 25%-40% of patients experiencing recurrence. To evaluate whether pre-treatment gut microbiome (GMB) features predict recurrence, we analyzed stool samples from 674 patients enrolled in a phase 3 clinical trial, CheckMate 915, which investigated the combination of nivolumab plus ipilimumab versus nivolumab as a single agent across five geographic regions. Region-specific and cross-region meta-analyses identified pre-treatment taxa associated with recurrence, including Eubacterium, Ruminococcus, Firmicutes, and Clostridium. Recurrence prediction was strongest when the validation cohort exhibited GMB profiles similar to those in the discovery cohort. Among closely matched individuals (Jensen-Shannon divergence [JSD] ≤ 0.11), the area under the curve (AUC) for recurrence prediction ranged from 0.78 to 0.94 across regions. GMB composition remained largely stable following treatment. These findings suggest that gut bacterial markers can predict recurrence after adjuvant ICB treatment in melanoma, supporting their potential as clinically actionable biomarkers to guide personalized therapy.
B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent fu...B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent function of B cells that spatially and metabolically drives exercise capacity. During exercise, B cell deficiency reduces transforming growth factor (TGF)-β1 production, which alters hepatic glutamate metabolism and decreases blood and muscle glutamate. Mechanistically, B cell-derived TGF-β1 transcriptionally upregulates hepatic glutaminase 2 (GLS2) and solute carrier family 7 member 5 (SLC7A5) expression, increasing glutamine catabolism and thus glutamate production in the liver. The resulting increase in glutamate fosters skeletal muscle calcium oscillations, calmodulin-dependent protein kinase (CaMK) kinase activity, and mitochondrial biogenesis, thereby improving exercise performance. Thus, we identify a metabolite-driven liver-muscle connection that regulates exercise capacity, linking B cell function to skeletal muscle calcium signaling via alteration of hepatic glutamate metabolism.
Microbiome science has greatly expanded our understanding of microbial life and its roles in the environment and human health. Yet microbiome science often relies on descriptive, correlation-based approaches that limit c...Microbiome science has greatly expanded our understanding of microbial life and its roles in the environment and human health. Yet microbiome science often relies on descriptive, correlation-based approaches that limit causal insight and intentional intervention designs. Moving toward predictive and mechanistic understanding requires functional characterization of microbial interactions and metabolic preferences. Here, we present microbial interaction and niche determination (MIND), which quantifies mRNA translation prioritization to infer substrate preferences and competitive interactions in complex communities. Applied to synthetic communities, soil, human fecal samples, and a mouse model, MIND predicted microbial competition and substrate preferences, guiding precision prebiotic and probiotic interventions to selectively modulate community composition. Currently focused on competition and substrate utilization, MIND could be further extended to capture additional interactions and ecological niches. By linking functional measurements to ecological outcomes, MIND offers a broadly applicable framework for targeted microbiome manipulation and rational intervention design rooted in functional insight.
Cyclic-oligonucleotide-based anti-phage signaling system (CBASS), a central prokaryotic antiviral strategy and evolutionary ancestor of the mammalian cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)...Cyclic-oligonucleotide-based anti-phage signaling system (CBASS), a central prokaryotic antiviral strategy and evolutionary ancestor of the mammalian cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, relies on cyclic-nucleotide-activated effectors to elicit immunity. The most prevalent effectors are transmembrane (TM) proteins, yet their mechanisms remain unknown. Here, we show how a representative three transmembrane (3TM)-SMODS-associated fused to various effector domains (SAVED) effector couples ligand sensing to membrane disruption. Upon binding 2'3'-cyclic GMP-AMP (cGAMP)-synthesized by bacterial cGAS/DncV-like nucleotidyltransferase (CD-NTase) with features resembling mammalian cGAS-3TM-SAVED assembles stepwise from an apo monomer through a transient dimer into extended filaments. Filament assembly employs 2'3'-cGAMP as molecular glue linking SAVED domains and reorients TM helices and amphipathic hairpins into vertically offset arrays. Both arrays bear opposing hydrophobic and hydrophilic faces, thereby driving vertical lipid shearing. This shearing generates a linear pore array that permeabilizes membranes and triggers cell death. These findings uncover the long-missing mechanism of CBASS TM effectors and establish vertical membrane shearing as an unrecognized principle of membrane disruption across domains of life.
Woo MS, Brand J, Bal LC
… +39 more, Moritz M, Walkenhorst M, Vieira V, Ipenberg I, Rothammer N, Wang M, Dogan B, Loreth D, Mayer C, Nagel D, Wagner I, Pfeffer LK, Landgraf P, van Ham M, Mattern KM, Winschel I, Frantz N, Sonner JK, Grosshans HK, Miguela A, Bauer S, Meurs N, Müller A, Binkle-Ladisch L, Salinas G, Jänsch L, Dieterich DC, Riedner M, Krüger E, Heppner FL, Glatzel M, Puelles VG, Engler JB, Nyengaard JR, Misgeld T, Kerschensteiner M, Merkler D, Meyer-Schwesinger C, Friese MA
Cancer therapy evolved from cytotoxic chemotherapy to targeted and immune treatments guided by molecular profiling. Early cytotoxic drugs, rooted in mustard-gas observations, remain effective but toxic. Targeted agents e...Cancer therapy evolved from cytotoxic chemotherapy to targeted and immune treatments guided by molecular profiling. Early cytotoxic drugs, rooted in mustard-gas observations, remain effective but toxic. Targeted agents exploit oncogenic vulnerabilities yet commonly select resistant clones. Checkpoint inhibitors and engineered modalities (ADCs, BiTEs, CAR-T) yield responses but are limited by toxicity and adaptive antigen loss. Future treatment combinations will require targeting the evolution of resistance. To view this SnapShot, open or download the PDF.
The hallmarks of cancer, first proposed in 2000, have since provided a unified framework for understanding the complexity of carcinogenesis. This conceptual model has profoundly influenced the treatment landscape of prim...The hallmarks of cancer, first proposed in 2000, have since provided a unified framework for understanding the complexity of carcinogenesis. This conceptual model has profoundly influenced the treatment landscape of primary liver cancer, which includes hepatocellular carcinoma (HCC, ∼85%) and intrahepatic cholangiocarcinoma (iCCA, 10%)-malignancies with high mortality. Key hallmarks exhibited by HCC include sustaining proliferative signaling, inducing or accessing vasculature, and avoiding immune detection. Over the past two decades, outcomes for patients with advanced HCC have significantly improved with immunotherapies. iCCA is characterized by hallmarks such as sustaining proliferative signaling, deregulating cellular metabolism, and avoiding immune detection. Unlike HCC, roughly 45% of iCCA harbor alterations amenable to precision oncology approaches, including fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, ERBB2 alterations, and BRAF mutations. In this review, we explore how this framework has reshaped liver cancer care and discuss the resulting breakthroughs in management and emerging directions that may further improve therapeutic strategies.
Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neur...Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neural reprogramming and neuropsychiatric symptoms that worsen patient outcomes. The field of cancer neuroscience seeks to unravel this complex neuro-cancer crosstalk and holds the promise to develop neuroscience-instructed cancer therapies that improve disease control and quality of life. Here, we summarize the key discoveries of neuro-cancer crosstalk to date, including neuron-to-cancer synapses and paracrine and neuro-immuno-oncological interactions, and then explore emerging topics such as downstream effects on cancer cell pathophysiology, circadian influences, brain-body-cancer communication, and neural regulation of the metastatic cascade and the tumor microenvironment. Finally, we distill overarching principles, highlight relevant ongoing research, and outline conclusions to guide the development of cancer neuroscience, proposing hypotheses for future experimental validation.
Tumors evolve within complex, adaptive ecosystems that operate across spatial, temporal, and systemic scales. Within each tumor microenvironment, numerous diverse cell populations assemble into specialized niches that ar...Tumors evolve within complex, adaptive ecosystems that operate across spatial, temporal, and systemic scales. Within each tumor microenvironment, numerous diverse cell populations assemble into specialized niches that are continually shaped by systemic physiology, environmental inputs, and therapeutic pressure. Beyond the local microenvironment, cancer progression is governed by the host macroenvironment, where intrinsic biological determinants intersect with modifiable factors to collectively impact physiological fitness and tissue resilience. Here, we propose a multi-scale framework that unites tumor biology with organismal physiology and reframes therapy from eliminating malignant cells in isolation to reprogramming the cellular, vascular, and systemic networks that sustain disease. We highlight emerging approaches that aim to restore physiological equilibrium, spanning from spatial multi-omics and AI-driven pathology to immune-vascular normalization and physiological conditioning. Together, these dimensions define an integrative vision for precision oncology that bridges discovery and intervention to achieve durable and ultimately curative cancer therapy.
Intratumor heterogeneity (ITH) encompasses genetic, epigenetic, transcriptional, proteomic, and immunopeptidomic diversity. Beyond genetic heterogeneity, it is increasingly clear that non-mutational heterogeneity and pla...Intratumor heterogeneity (ITH) encompasses genetic, epigenetic, transcriptional, proteomic, and immunopeptidomic diversity. Beyond genetic heterogeneity, it is increasingly clear that non-mutational heterogeneity and plasticity generate dynamic cancer cell states with distinct immune visibility. These layers of complexity converge on the immunopeptidome, the repertoire of peptides displayed by major histocompatibility complex molecules through which tumor cells are surveyed by T cells. Variation in antigen processing, presentation, and peptide abundance across cancer clones and cell states yields spatially and temporally distinct immunological niches that shape immune recognition and therapeutic response. Here, we summarize how multidimensional ITH manifests across cancer types and constrains immunotherapy efficacy. We propose that integrating measurements across layers is a promising direction for improving biomarker identification and informing more precise immune-based treatment strategies.
Tumors acquire blood vessels primarily via sprouting angiogenesis and co-option of pre-existing host vasculature, but also via intussusception, vasculogenesis from bone-marrow-derived progenitors, vascular mimicry, and e...Tumors acquire blood vessels primarily via sprouting angiogenesis and co-option of pre-existing host vasculature, but also via intussusception, vasculogenesis from bone-marrow-derived progenitors, vascular mimicry, and endothelial transdifferentiation. The abnormal structure and function of these vessels, resulting from an imbalance between pro- and anti-angiogenic signaling as well as from the physical forces, impair the delivery and efficacy of therapeutics. We review the evolving narrative of targeting angiogenesis from starving tumors to vascular normalization as a therapeutic principle and highlight recent spatial-omics revelations and the emerging role of neural, microbial, hormonal, and chronological factors. We elaborate on the molecular mechanisms of tumor vessel formation, how dysfunctional vessels cause an abnormal tumor microenvironment characterized by hypoxia, low pH, elevated fluid pressure, and immunosuppression, and how vascular normalization enhances the delivery and efficacy of various therapies, including immunotherapies, and has formed the basis of emerging strategies and novel therapeutic agents to improve patient outcomes.
"Evasion of cell death" is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell de..."Evasion of cell death" is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell death programs. Over the past two decades, the cell death field has expanded from apoptosis to include necroptosis, pyroptosis, ferroptosis, and other emerging programs, reshaping cancer biology and revealing therapeutic opportunities. While apoptosis remains the primary radiation- and chemotherapy-induced cell death program, non-apoptotic programs can drive inflammatory responses and orchestrate the interplay among tumor, stroma, and immune components, influencing immunotherapy outcomes. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death modality, lacks a canonical induction signal and arises from perturbations in lipid, iron, and redox metabolism. This review presents a unified framework for understanding the roles of major cell death programs in cancer development, progression, and treatment response, as well as addressing resistance to cancer cell death and immune suppression. "Our bodies are made of cells that live, and just as surely, of cells that must die." -S. Brenner.
Some aggressive cancers exhibit a level of rapid genome change and therapy resistance that is difficult to explain. Research over the past decade has shown that extrachromosomal DNA (ecDNA) can be the cause. When oncogen...Some aggressive cancers exhibit a level of rapid genome change and therapy resistance that is difficult to explain. Research over the past decade has shown that extrachromosomal DNA (ecDNA) can be the cause. When oncogenic genetic elements untether from chromosomes and no longer follow Mendelian inheritance, genomic chaos and accelerated evolution ensue, generating unique ecDNA biology and non-traditional therapeutic vulnerabilities distinct from traditional mutation-targeting approaches. Here, we put forward a holistic view where ecDNA is integrated into the broader Hallmarks of Cancer framework to better understand the problem and chart a path forward.
Genomic instability is a defining feature of cancer, which arises when the cellular systems that maintain DNA integrity falter, enabling the accumulation of genetic and epigenetic alterations that drive malignant transfo...Genomic instability is a defining feature of cancer, which arises when the cellular systems that maintain DNA integrity falter, enabling the accumulation of genetic and epigenetic alterations that drive malignant transformation. It is both the architect of cancer's evolution and its Achilles' heel. Targeting genomic instability has reshaped oncology: first through systemic chemotherapy and external beam radiation and then with poly(ADP-ribose) polymerase (PARP) inhibitors in homologous recombination repair-deficient tumors and other DNA damage response targets. Recently, tumor-targeted DNA-damaging platforms, namely antibody-drug conjugates (ADCs) and radiopharmaceuticals, have emerged alongside modern precision medicine strategies to optimize patient selection, develop rational combinations, and widen the therapeutic index.
Cancer in younger adults is rising globally, with notable birth-cohort effects. This epidemiological shift underscores the urgent need to accelerate the identification of novel causes and underlying biological networks,...Cancer in younger adults is rising globally, with notable birth-cohort effects. This epidemiological shift underscores the urgent need to accelerate the identification of novel causes and underlying biological networks, with the aim of translating these insights into prevention and interception strategies. In this perspective, we revisit the major milestones in the discovery of cancer causes and outline challenges that hinder progress. To address these challenges, we advocate closer integration of epidemiologic and mechanistic studies and propose three interconnected frameworks that extend current epidemiologic approaches: a tissue ecosystem-anchored framework for cancer cause discovery, a biological state-based framework for precision cancer risk assessment, and a dynamic framework to characterize cancer preventability. This roadmap aims to stimulate conceptual, resource, and methodological advances to accelerate cancer etiology research and prevention in the era of rising early-onset cancers.