The Hallmarks of Cancer framework has played a seminal role in developing our understanding of cancer biology. By design, these hallmarks abstract cancer into a common set of functional capabilities. The hallmarks thus c...The Hallmarks of Cancer framework has played a seminal role in developing our understanding of cancer biology. By design, these hallmarks abstract cancer into a common set of functional capabilities. The hallmarks thus constitute an intentionally reductionist framework that has unified diverse observations and yielded valuable mechanistic insight, while leaving unresolved how these processes interact across scales. Complementary tools are therefore needed to capture cancer's inherently complex, multimodal, and multiscale nature. Here, we posit that generative models, built on the recent advances of artificial intelligence, are the key technology to capture this complexity and to thereby improve how we diagnose, understand, and intervene in cancer. Specifically, because of their ability to recognize complex patterns, process unstructured inputs, and synthesize multimodal inputs, generative models are poised to usher in a new era of biological discovery and clinical care. Ultimately, we envision a synergistic cycle wherein generative models of cancer and the Hallmarks of Cancer complement one another, the former driving hypothesis generation and discovery and the latter guiding the prioritization and development of new measurement tools.
Since the original Hallmarks of Cancer, our understanding of the complexity of the disease has expanded dramatically. Researching cancer is no longer simply a question of ever more sophisticated experiments but of delive...Since the original Hallmarks of Cancer, our understanding of the complexity of the disease has expanded dramatically. Researching cancer is no longer simply a question of ever more sophisticated experiments but of delivering science in an evolving and complex system. Here, we discuss how to support global team science and catalyze transformative discovery, drawing on our experience from the Cancer Grand Challenges initiative.
Patient advocacy has the potential to contribute to effective cancer care with real-world impact, regardless of a country's socioeconomic status. Here, we asked representatives of patient advocacy groups for key consider...Patient advocacy has the potential to contribute to effective cancer care with real-world impact, regardless of a country's socioeconomic status. Here, we asked representatives of patient advocacy groups for key considerations to overcome challenges when starting out in resource-limited settings. We are grateful to them for sharing their voices and for their relentless fight toward making cancer care more accessible.
In this Voices piece, we asked researchers to reflect on how the Hallmarks of Cancer have shaped their career paths, their research directions, and their broader perspectives on cancer. Their reflections show how the fra...In this Voices piece, we asked researchers to reflect on how the Hallmarks of Cancer have shaped their career paths, their research directions, and their broader perspectives on cancer. Their reflections show how the framework continues to guide discovery, encourage collaboration across disciplines, and inspire new ways to better understand and treat cancer.
In choosing to merge two independent teams, we stepped into an unconventional model of co-leadership that reshaped our scientific lives. A clinician and a scientist leading together challenged academic norms, dissolved t...In choosing to merge two independent teams, we stepped into an unconventional model of co-leadership that reshaped our scientific lives. A clinician and a scientist leading together challenged academic norms, dissolved the loneliness of traditional principal investigator roles, and created a shared patient-centered vision for translational research. By embedding patients, carers, and high-performance coaching at our core, we built a culture defined not by individual burden but by collective responsibility, sustainability, and genuine collaboration. This is our story.
Twenty-five years after its publication, the Hallmarks of Cancer framework continues to illuminate tumor biology and drive therapeutic innovation. This special issue surveys how the concept has shaped our understanding o...Twenty-five years after its publication, the Hallmarks of Cancer framework continues to illuminate tumor biology and drive therapeutic innovation. This special issue surveys how the concept has shaped our understanding of cancer, guided drug development, and evolved to incorporate new discoveries and address emerging challenges.
Thornburg ZR, Maytin A, Kwon J
… +15 more, Brier TA, Gilbert BR, Fu E, Gao YL, Quenneville J, Wu T, Li H, Long T, Pezeshkian W, Sun L, Bittencourt DMC, Glass JI, Mehta AP, Ha T, Luthey-Schulten Z
Reyes J, Del Priore I, Chaikovsky AC
… +22 more, Pasnuri N, Elhossiny AM, Park J, Weiler P, Krause T, Moorman A, Snopkowski C, Takizawa M, Burdziak C, Ratnayeke N, Masilionis I, Ho YJ, Chaligné R, Romesser PB, Filliol A, Nawy T, Morris JP, Zhao Z, Pasca Di Magliano M, Alonso-Curbelo D, Pe'er D, Lowe SW
The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic...The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.
de Launoit E, Skriabine S, Doumazane E
… +17 more, Bizou M, Pommé R, Lienhard G, Rajot D, Mikhailenko A, Vieites-Prado A, Lannes M, Fabiano N, Mathé L, Cagnone G, Mouton L, Santin MD, Candelier S, Gaspar P, Rousseau CV, Dubrac A, Renier N
The structure of the cerebral vasculature is immature at birth and undergoes significant postnatal remodeling and expansion. However, how vascularization progresses throughout the brain to integrate volumetric growth wit...The structure of the cerebral vasculature is immature at birth and undergoes significant postnatal remodeling and expansion. However, how vascularization progresses throughout the brain to integrate volumetric growth with neuronal circuit maturation is unclear. To address this spatiotemporally, we developed a light-sheet-aligned mouse brain annotated developmental atlas (LAMBADA)-a resource for registering and annotating optically cleared developing mouse brains with high temporal resolution, enriched by aligned spatial transcriptomics. Using this resource, we identified three distinct, brain-wide phases of postnatal cerebral vascular development: (1) an isometric expansion phase characterized by canonical transcriptomic signatures; (2) a regional specialization phase coinciding with neuronal maturation and synaptogenesis; and (3) a refinement phase marked by the stabilization of vascular networks and synapses. We delineated the molecular and structural mechanisms underlying these phases by correlating vascular remodeling with spatial transcriptomic gene expression. This atlas provides a foundation for studying developmental neurovascular interactions and serves as a resource for murine postnatal brain development research.
Gaining precise control of gene expression is crucial in biomedical applications. However, spatiotemporal precision remains challenging. Here, we present a remotely controlled in vivo gene switch responsive to electromag...Gaining precise control of gene expression is crucial in biomedical applications. However, spatiotemporal precision remains challenging. Here, we present a remotely controlled in vivo gene switch responsive to electromagnetic fields (EMFs) that enables precise spatiotemporal activation of target genes. We uncovered the EMF-inducible gene switch activation mechanism via a CRISPR-Cas9 screen, identifying cytochrome b5 type B (Cyb5b) as an essential mediator likely acting as an EMF sensor. The EMF-inducible gene switch was activated by rhythmic oscillatory calcium dynamics rather than generic calcium influx, defining a precisely tuned and bio-orthogonal induction mechanism. Functionally, EMF activation of the Oct4-Sox2-Klf4 (OSK) cassette induced in vivo partial reprogramming in aged mice, conditional expression of human mutant amyloid precursor protein (APP) for Alzheimer's disease (AD) modeling recapitulated pathological features, and EMF-mediated Tph2 expression restored serotonergic activity and ameliorated depressive-like behaviors in Tph2-mutant depression mice. Overall, a remotely controlled EMF-inducible gene switch represents a versatile and effective biomedical platform.
The cannabinoid receptor 1 (CB1) has emerged as a promising candidate for next-generation non-opioid therapies. However, the development of therapeutics targeting CB1 has been consistently hindered by significant adverse...The cannabinoid receptor 1 (CB1) has emerged as a promising candidate for next-generation non-opioid therapies. However, the development of therapeutics targeting CB1 has been consistently hindered by significant adverse effects. Here, through structure-activity relationship analyses focused on biased signaling, we rationally design two G-biased CB1 agonists, LZD503 and LZD505. Our design strategy employed structural spatial tuning of the agonist scaffold to disrupt specific molecular interactions and minimize steric conflicts with critical tip residues within the ligand-binding pocket, thereby promoting preferential G-pathway signaling. Cryo-electron microscopy structures of the CB1-G-protein complexes bound to these designed agonists confirmed that their anticipated conformational poses favored G-biased signaling. Both designed compounds demonstrated promising results by alleviating pain and mitigating unwanted responses in mice. The elucidated CB1 complex structures and the resulting insights establish a comprehensive framework for the structure-guided development of innovative CB1-targeted analgesics with reduced adverse effect profiles.
Ndoja A, Reja R, Lee SH
… +11 more, Webster JD, Ngu H, Rose CM, Kirkpatrick DS, Modrusan Z, Jasmine Chen YJ, Dugger DL, Gandham V, Xie L, Newton K, Dixit VM
Cellular senescence is a conserved stress-responsive program defined by durable proliferative arrest and extensive remodeling of chromatin, metabolism, intercellular signaling, and immune interactions. Initially describe...Cellular senescence is a conserved stress-responsive program defined by durable proliferative arrest and extensive remodeling of chromatin, metabolism, intercellular signaling, and immune interactions. Initially described as a barrier to unlimited cell division, senescence is now recognized as a pleiotropic and heterogeneous biological process with roles in development, tissue repair, immune surveillance, tumor suppression, aging, fibrosis, and cancer progression. Despite its broad relevance, senescence remains challenging to define operationally, as its molecular features, functional outputs, and physiological consequences vary across cell types, tissues, and stimuli. This review summarizes core hallmarks of senescence while synthesizing how these features are differentially engaged, diversified, and repurposed across biological contexts. Focusing on cancer, we discuss how senescence influences tumor initiation, evolution, and therapeutic response through both cell-intrinsic and microenvironmental mechanisms. We further evaluate emerging strategies to therapeutically modulate senescence, highlighting both opportunities and unresolved challenges for precision intervention.
Traditional animal-based drug discovery has high failure rates, prompting the search for and adoption of human-centered new approach methodologies (NAMs). Rapid advances in stem cell-, organoid-, and in silico-based NAMs...Traditional animal-based drug discovery has high failure rates, prompting the search for and adoption of human-centered new approach methodologies (NAMs). Rapid advances in stem cell-, organoid-, and in silico-based NAMs, supported by evolving frameworks from the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), now span the entire drug-discovery continuum, from disease modeling and drug design to efficacy testing. Our review highlights recent progress across these domains, including the identification of therapeutic candidates, the development of cutting-edge models and technologies, and the potential of NAMs themselves as treatments in preclinical and clinical contexts, while examining the key biological, technical, and regulatory bottlenecks that need to be addressed to enable robust translational adoption. We conclude by discussing the translational and societal considerations essential to the responsible adoption of NAMs and outlining future human-centric pipelines poised to redefine the landscape of drug discovery.
Artificial intelligence has rapidly advanced molecular science, yet progress has largely unfolded through specialized models tailored to specific tasks. In this issue of Cell, Peng et al. introduce PocketXMol, a unified...Artificial intelligence has rapidly advanced molecular science, yet progress has largely unfolded through specialized models tailored to specific tasks. In this issue of Cell, Peng et al. introduce PocketXMol, a unified 3D generative framework that reframes molecular design problems as conditional reconstruction of atomic interactions. Demonstrations across design scenarios highlight its potential in molecular engineering.
Nicotine, tobacco's addictive and potent insecticidal alkaloid, has shaped human history, agriculture, and the plants that produce it. However, the enzymatic steps and reaction mechanisms involved in nicotine biosynthesi...Nicotine, tobacco's addictive and potent insecticidal alkaloid, has shaped human history, agriculture, and the plants that produce it. However, the enzymatic steps and reaction mechanisms involved in nicotine biosynthesis remain elusive. Here, we reveal that the final coupling reaction is stabilized by glycosylation via a uridine diphosphate (UDP)-glycosyltransferase, reduced and activated by an A622, condensed through a stereoselective intermolecular Mannich-like reaction, sequentially oxidized by a berberine bridge enzyme-like (BBL), and finally deglycosylated by a β-glucosidase to yield nicotine. A 5-component metabolon assembles at vacuolar membranes to channel both nicotine biosynthesis and its transport. We reconstituted this metabolon both in vitro and heterologously in vivo. Abrogating any of these components depletes nicotine accumulations. A multidrug and toxic compound extrusion (MATE) transporter is essential for efficiently engineering nicotine production in heterologous plant species, which confers pest resistance. This work completes the nicotine biosynthesis pathway and provides critical insights into the intermolecular Mannich-like reaction, a fundamental mechanism for scaffold formation in many plant alkaloids.
Caire R, Bordo R, Zanconato F
… +30 more, Panciera T, Audoux E, Contessotto P, Fakiola M, Bason R, Romano O, Suli A, Battilana G, Marchionni M, Forcato M, Donzelli S, Dieci MV, Griguolo G, Carosi M, Fassan M, Guzzardo V, Dei Tos AP, Marsoni S, Wu PH, Wirtz D, He S, Casali C, Volpin F, Blandino G, Tripodo C, Bicciato S, Guarneri V, Pagani M, Cordenonsi M, Piccolo S
The tissue-level processes underpinning metastatic outgrowth remain unclear. We combined single-cell RNA sequencing, spatial transcriptomics, and AI-supported 3D imaging in human breast cancer with functional investigati...The tissue-level processes underpinning metastatic outgrowth remain unclear. We combined single-cell RNA sequencing, spatial transcriptomics, and AI-supported 3D imaging in human breast cancer with functional investigations in mice to uncover a 3D morphogenetic process essential for macrometastatic expansion. Macrometastases pervasively activate a metastatic trabecular morphogenesis (MTM) gene-expression program that redeploys developmental branching morphogenesis to build macrometastases as a 3D trabecular lattice of epithelial cords. MTM cells pre-exist in primary tumors destined to metastasize, whereas MTM primaries are non-metastatic and display a compact, expansile growth architecture. Chromatin immunoprecipitation sequencing (ChIP-seq) on metastatic organoids identifies ETV1/4/5 as master regulators of MTM and branching cancer morphogenesis, required for metastatic outgrowth but dispensable for primary tumor take, bulk growth, and initial metastatic dissemination. Spatial and functional analyses reveal stromal fibroblast growth factor (FGF)→fibroblast growth factor receptor (FGFR) signaling as an actionable MTM dependency. Thus, we link metastatic outgrowth to a 3D developmental morphogenetic process, exposing therapeutic vulnerabilities specific to the lethal macrometastatic stage.
Many viruses can switch between lytic replication and dormancy (or lysogeny). It was recently discovered that some viruses that infect bacteria (known as bacteriophage or phage) employ peptide-based ("arbitrium") communi...Many viruses can switch between lytic replication and dormancy (or lysogeny). It was recently discovered that some viruses that infect bacteria (known as bacteriophage or phage) employ peptide-based ("arbitrium") communication systems to optimize their lysis/lysogeny switch; high peptide concentrations signal a lack of susceptible hosts and trigger lysogeny, while low peptide concentrations signal an abundance of uninfected hosts and prompt lysis. Here, we demonstrate that arbitrium phages belonging to different species and genera can influence each other's infection dynamics by secreting similar communication peptides, leading to early lysogenization of the signal-receiving phage and elevated fitness of the signal-emitting phage. Antagonistic coevolution between signal-emitting and signal-receiving phages to manipulate each other's infection behaviors may explain the rapid diversification of arbitrium systems and their frequent horizontal exchange to escape the noise of crosstalk.
Arbitrium is a communication system that helps bacteriophages to decide between lysis and lysogeny through secreted peptides. In this system, the arbitrium communication peptide (AimP) binds its cognate arbitrium recepto...Arbitrium is a communication system that helps bacteriophages to decide between lysis and lysogeny through secreted peptides. In this system, the arbitrium communication peptide (AimP) binds its cognate arbitrium receptor (AimR) to repress aimX (a negative regulator of lysogeny) expression, promoting lysogeny. It has been assumed that each AimR responds exclusively to its own AimP. Here, we challenge this view by demonstrating cross-communication between arbitrium systems. Using prototypical arbitrium phages, we show that AimP peptides can bind and repress non-cognate AimR receptors, promoting lysogeny and reducing prophage induction. Structural and biochemical analyses reveal conserved receptor features that permit cross-recognition of non-cognate peptides while preserving recognition of cognate partners. In mixed lysogenic cultures, these interactions alter induction outcomes, underscoring their ecological significance. Extending to infection contexts, we demonstrate that crosstalk favors lysogeny of incoming phages in cells harboring compatible systems. These findings establish that phages engage in cross-species communication via peptide signaling, reshaping microbial communities in unexpected ways.