Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

URI permanent per a aquesta col·leccióhttps://hdl.handle.net/2445/98743

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Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle
(2026-06-11) Kandyba, Eve; Jabouille, Arnaud; Calvet, Ferriol; Li, Yun Rose; Curtabbi, Andrea; Cristea, Diana; Shin, Joyce; Delrosario, Reyno; Anzules, Jonathan; Wu, Di; Quigley, David; Taylor, Mark; Zanette, Camila; Lo, Fang Yin; Higgins, Jacob; Salk, Jesse; Lopez Bigas, Nuria; Balmain, Allan
The identification of the cancer cell of origin is a fundamental question in cancer biology. We used fluorescent lineage tracing of independent mouse skin stem cell populations, single cell transcriptomics, and Duplex sequencing, to identify the origin of chemically induced skin tumors. Tumors arose predominantly from Lgr6+ and / or Lrig1+ stem cells of the upper hair follicle, but only very rarely from the Lgr5+ and Krt19+ hair follicle bulge. Lgr6+ stem cells initiated by dimethylbenzanthracene responded to tumor promoter treatment resulting in clonal expansion of initiated cells carrying the canonical Hras Q61L mutation. Spontaneous mutations in Kras also clonally expanded, but did not generate tumors unless the Hras gene was deleted, thus revealing a competitive interaction between Hras and Kras pathways that influences clonal selection.
MRP8-Cre Transgenic Mice Are Resistant to Weight Gain and Diet-Induced Obesity Independently of Neutrophils
(John Wiley & Sons, 2026-09-16) Forisch, Stephan; Soltani, Fatemeh; Salvat Costa, Laia; Marques Cardoso, Beatriz Joana; Moreno Galiano, Yaiza; Duval, Cedric; Ariëns, Robert A. S.; Chandel, Navdeep S.; Kaartinen, Mari T.; Wculek, Stefanie Kristin
Obesity is a major risk factor for metabolic syndrome, cancer, diabetes, and other diseases. The occurrence of comorbidities is associated with systemic and adipose tissue inflammation, which is marked by the presence of macrophages and neutrophils in adipose tissue. The role of neutrophils in driving adipose tissue inflammation and pathology is understudied and may hold therapeutic promise. MRP8Cre transgenic mice are frequently used to investigate neutrophil functions. A recent report demonstrates that the insertion of the MRP8Cre transgene resulted in whole-body deletion of Ap1s1 and Serpine1, the latter encoding the pro-obesogenic factor plasminogen activator inhibitor-1 (PAI-1). Here, we show that MRP8Cre transgenic mice have lower body weight than their littermate controls on a standard chow diet. Furthermore, they are resistant to weight gain, adipose tissue hypertrophy, systemic deregulation of glucose metabolism, infiltration of macrophages into AT, and liver steatosis upon feeding of obesogenic, high-fat diets (HFD). Mechanistically, this was independent of neutrophils or bone marrow-derived cells, sex, age of the mice, the duration of the HFD feeding, treatment start, housing facility, or the original source of the mice. The expression of Sepine1/PAI-1 and Ap1s1 is globally reduced across metabolic organs of MRP8Cre mice irrespective of diet, thus phenocopying previous reports of the obesity-protective effect of PAI-1 depletion in mice. Our findings demonstrate the limited applicability of MRP8Cre mice for obesity or metabolic studies due to the observed off-target effects and highlight the need for respective controls when using transgenic mice, such as Cre-only controls or use of independent Cre lines for studies involving the Cre/loxP system.
Targeted KRASG12V Degradation in vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis
(American Association for Cancer Research, 2026-08-14) Martín Cardona, Albert; García-Pérez, Inés M.; San José, Sonia; Rojo, Pep; Riego Mejías, Carlos; Teodosio, Cristina; Barbosa, Bárbara M. G.; Sánchez Zarzalejo, Carolina; Folch i Casanovas, Ignasi; Odena Caballol, Antonia; Jarió Ruana, Sònia; Hijazo Pechero, Sara; Rodríguez-López, Silvia; Entrialgo-Cadierno, Rodrigo; Nokin, Marie-Julie; Muñoz Félix, José Manuel; Loa-Mesón, Diana; Guruceaga, Elisabeth; Stephan-Otto Attolini, Camille; Ambrogio, Chiara; Villanueva Garatachea, Alberto; Vicent, Silvestre; Riera Mestre, Antoni; Santamaria, David; Mayor-Ruiz, Cristina
Recent drug discovery breakthroughs led to the approval of KRASG12C inhibitors in lung adenocarcinoma (LUAD). Unfortunately, clinical responses are often hampered by the rapid resistance onset. Proteolysis-targeting chimeras (PROTACs) have emerged as promising alternatives to traditional inhibition. However, there is limited mechanistic understanding of KRAS degradation in vivo. Here, we developed a preclinical LUAD mouse model and demonstrated that targeted oncogenic KRAS degradation induces rapid tumor regression primarily due to cancer cell-autonomous mechanisms. Yet, transcriptional, histological, and immunophenotypic analyses revealed a substantial remodeling of the tumor microenvironment. Notably, disease relapse observed during prolonged PROTAC treatment stemmed mostly from proteolysis machinery dysregulation, indicating resistance mechanisms distinct from those reported upon KRAS inhibition. Collectively, these findings highlight the therapeutic potential of KRAS degradation in LUAD, providing insights into both cell-intrinsic and -extrinsic mechanisms that accompany antitumor responses and support the ongoing clinical exploration of this approach.
Noncircadian BMAL1-YAP activity amplifies persistent inflammation in aged epidermis
(Springer Nature, 2026-08-19) BONJOCH LOBERA, Júlia; Sola Castrillo, Paloma; GARCIA MULERO, SANDRA; Mortimer, Thomas; Reina García, Oscar; Stephan-Otto Attolini, Camille; Miroshnikova, Yekaterina A; Wickstrom, Sara A; ALVAREZ RODRIGUEZ, Laura; Aznar Benitah, Salvador; Solanas Fuster, Guiomar
Aging is characterized by persistent low-grade inflammation linked to impaired tissue homeostasis, yet the underlying molecular mechanisms remain poorly understood. The mammalian skin is a clinically relevant site of aging-driven inflammation associated with compromised barrier function, inefficient wound healing, elevated oxidative stress and DNA damage accumulation. Here we show that, in the murine epidermis, aging engages a previously uncharacterized BMAL1-YAP functional cooperation with enhanced binding at inflammation-related enhancers, amplifying target gene transcription. Independent of its circadian clock role, BMAL1 partners with the mechanosensitive cofactor YAP at enhancer regions to regulate epidermal identity genes. However, in aged skin, this cooperative binding undergoes a functional shift, enhancing the expression of inflammation-related genes, partially coregulated by NF-kappa B. In addition, aged pro-inflammatory IL-17 signaling activates YAP in a Hippo-independent manner. These findings unveil a transcriptional mechanism underlying epidermal aging, linking chromatin dynamics to inflammatory programs through rewiring of BMAL1-YAP-occupied enhancers, highlighting potential strategies to counteract chronic inflammation and restore tissue homeostasis during aging.
hexABC seeking the physical code of DNA
(Nature Publishing Group, 2026-06-24) Battistini, Federica; Wieczór, Miłosz; Hospital Gasch, Adam; Pasi, Marco; Arcon, Juan Pablo; Serrano Chacón, Israel; Sala Huerta, Alba; Deb, Subhamoy; García-Doñate, Agustín; Burman, Matthew; Chan, Elliot W.; Chang, Liwei; da Rosa, Gabriela; Espinosa, Jorge R.; Hoang, Gia Linh; Hossain, Kazi A.; Jurkowski, Michał; Poupon, Romain; Sharma, Rahul; Sun, Ran; Bishop, Thomas C.; Carloni, Paolo; Cheatham III, Thomas E.; Collepardo Guevara, Rosana; Czub, Jacek; Dans, Pablo D.; Harris, Sarah A.; Laughton, Charles; Galindo-Murillo, Rodrigo; Maddocks, John H.; Noy, Agnes; Pérez, Alberto; Petkevičiūtė-Gerlach, Daiva; Orozco López, Modesto
We present a tour de force of atomistic molecular dynamics simulations involving the coordinated effort of 14 research groups of the Ascona B-DNA Consortium (ABC). This initiative provides a complete characterization of the 2080 DNA hexamers embedded in 190 carefully selected 20-mer duplexes, each simulated in replicate for at least 10 microseconds in explicit solvent. The consortium generates 0.25 petabytes of data, capturing millisecond-scale ensembles at the oligomer level and dynamics up to 10−1 seconds at the base-pair level. Analysis yields a comprehensive description of sequence-dependent DNA properties, including rare events such as backbone transitions, reversible base-pair changes, and partial unfolding. Processing these atomistic ensembles reveals a hidden physical code of DNA, helping explain rules of genome composition and evolution beyond coding regions. This community effort delivers unprecedented, validated FAIR data to support coarse-grained and AI models of DNA at cellular scale.
The conserved lysine residue in transmembrane helix 5 is pivotal for the cytoplasmic gating of the L- amino acid transporters
(Oxford University Press, 2025-01-01) Llorca, Oscar; Orozco López, Modesto; Cordes, Thorben; Palacín Prieto, Manuel; Fort, Joana; Nicolàs Aragó, Adrià; Maggi, Luca; Martinez-Molledo, Maria; Kapiki, Despoina; González Novoa, Paula; Gómez Gejo, Patricia; Zijlstra, Niels; Bodoy i Salvans, Susanna; Pardon, Els; Steyaert, Jan
L-Amino acid transporters (LATs) play a key role in a wide range of physiological processes. Defects in LATs can lead to neurological disorders and aminoacidurias, while the overexpression of these transporters is related to cancer. BasC is a bacterial LAT transporter with an APC fold. In this study, to monitor the cytoplasmic motion of BasC, we developed a single-molecule Förster resonance energy transfer assay that can characterize the conformational states of the intracellular gate in solution at room temperature. Based on combined biochemical and biophysical data and molecular dynamics simulations, we propose a model in which the conserved lysine residue in TM5 supports TM1a to explore both open and closed states within the cytoplasmic gate under apo conditions. This equilibrium can be altered by substrates, mutation of conserved lysine 154 in TM5, or a transport-blocking nanobody interacting with TM1a. Overall, these findings provide insights into the transport mechanism of BasC and highlight the significance of the lysine residue in TM5 in the cytoplasmic gating of LATs.
Spatiotemporal T-cell tracking for personalized T-cell receptor T-cell therapy designs in childhood cancer
(2025-09-01) Sentís, Inés; Melero Ollonarte, Juan Luis; Cebria Xart, Alex; Grzelak, M.; Soto Gimeno, Marta; Michel, Angelika; Rovira Castellà, Quirze; Rodriguez Hernández, Cristóbal José; Caratu, Ginevra; Urpi, Andrea; Sauvage, C.; Mendizábal Sasieta, Ana; Maspero, Davide; Lavarino, Cinzia; Pascual Reguant, Anna; Castañeda Heredia, Alicia; Muñoz Pérez, J. P.; Mora Graupera, Jaume; Harari, A.; Nieto, Juan C.; Avgustinova, Alexandra; Heyn, Holger
Background: Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers. Patients and methods: We present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized T-cell receptor T-cell (TCR-T) therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T-cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood. Results: Tracking T-cell dynamics longitudinally from the tumor to cells in circulation over a time course of 12 months revealed a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T-cell dynamics in the blood post-ICI to predict tumor reactivity. Conclusions: These findings strongly support spatiotemporal tracking of T-cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.
Fibroblastic aspartoacylase suppresses TGFβ-mediated responses and cancer progression
(Springer Nature, 2026-06-16) Astobiza, Ianire; Capó Serra, Catalina; Viera, Cristina; Rodriguez, Javier; Carnicero, Patricia; Juliá, Miguel; Martinez, Ainara; Pérez López, Carmen; Subijana, María; Ortiz Sanz, Carolina; Garcia Longarte, Saioa; Mendizabal, Isabel; Kay, Emily J.; Riera Domingo, Carla; Rivis, Silvia; Carlevaris, Onintza; Egia Mendikute, Leire; Cascais, Sara; Martín Martín, Natalia; Fernández Ruiz, Sonia; Torrano, Veronica; Crespo, Jana R.; Pujana Vaquerizo, Mikel; Espinet, Elisa; Trumpp, Andreas; Eiro, Noemi; Vizoso, Francisco J.; Vivancos, Ana; Seoane, Joan; Gonzalo, David; Rey, Sofía; Santos Martín, Aida; Ugalde Olano, Aitziber; Manini, Claudia; López, Jose I.; Cabrera, Diana; Van Liempd, Sebastian M.; Falcon Perez, Juan M.; Gomis Cabré, Roger; Palazón, Asís
Glycogen drives the sensory activation of POMC neurons
(Nature Publishing Group, 2026-05-27) Gómez-Valadés, Alicia G.; Meseguer, David; Varela, Luis; Lienhard, Gabriele; Fernández, Uxía; Vidal Itriago, Andrés; Toledo Soler, Miriam; Eyre, Elena; Laudo, Berta; Díaz Castro, Francisco; Pozo, Macarena; Boutagouga Boudjadja, Mehdi; Fos Domènech, Júlia; García Ramón, Pau; Ferreira, Mariana; Altirriba Gutiérrez, Jordi; Beiroa, Daniel; Chen, Bandy; Rodríguez Díaz, Amanda; Milà Guasch, Maria; Chivite, Íñigo; Obri, Arnaud; Ramírez, Sara; Haddad Tovolli, Roberta; Tahiri, Iasim; Gentry, Matthew S.; Agostino, Giuseppe D'; Nogueiras, Rubén; Renier, Nicolas; Horvath, Tamas L.; Guinovart, Joan J. (Joan Josep), 1947-2025; Duran Castells, Jordi; Schneeberger, Marc; Claret i Carles, Marc
Hypothalamic POMC neurons modulate systemic energy balance and glucose homeostasis by sensing nutritional state signals. In addition to this classic regulatory mode, these neurons are also activated by the sensory perception of food. Here, we report that food-related sensory cues engage glycogen metabolism in POMC neurons. Genetic depletion of glycogen through various approaches renders POMC neurons unresponsive to food-associated sensory stimuli. This defective perception of food is linked to alterations in consummatory behaviour, hepatic adaptations and cephalic insulin release associated with a prediabetic phenotype that progresses into overweight and overt diabetes with a high-calorie diet or ageing. Collectively, our results posit glycogen as a decisive fuel resource for meeting the rapid and demanding energy requirements linked with sensory activation. Furthermore, our data delineate the biological function of food perception and provide support for the physiological relevance of neuronal glycogen.
Global genetic interaction network of a human cell maps conserved principles and informs functional interpretation of gene co-essentiality profiles
(Elsevier B. V., 2026-04-27) Billmann, Maximilian; Costanzo, Michael; Zhang, Xiang; Hassan, Arshia Z.; Rahman, Mahfuzur; Brown, Kevin R.; Chan, Katherine S.; Tong, Amy Hin Yan; Pons Pérez, Carles; Ward, Henry N.; Ross, Catherine; van Leeuwen, Jolanda; Aregger, Michael; Lawson, Keith A.; Mair, Barbara; Roth, Amy F.; Sen, Nesli E.; Forster, Duncan T.; Tan, Guihong; Mero, Patricia; Masud, Sanna N.; Lee, Yoonkyu; Aguilera Uribe, Magali; Usaj, Matej; Almeida, Sylvia M.T.; Aulakh, Kamaldeep; Bhojoo, Urvi; Birkadze, Saba; Budijono, Nathaniel; Cai, Xunhui; Caumanns, Joseph J.; Chalmers, Jordan J.; Chandrashekhar, Megha; Chang, Daniel; Climie, Ryan; Dasgupta, Kuheli; Drazic, Adrian; Rojas Echenique, Jose I. ; Gacesa, Rafael; Granda Farias, Adrian
Deciphering how genes interact within human cells is essential for understanding their functional wiring and for developing targeted therapeutic strategies. In this study, we present a genome-scale map of genetic interactions in the human haploid cell line HAP1, based on CRISPR-based perturbation of ∼4 million gene pairs. The resulting network comprises ∼89,000 high-confidence gene-gene interactions, organizing genes into hierarchical modules corresponding to protein complexes and pathways, biological processes, and cellular compartments, mirroring principles observed in yeast and highlighting the functional architecture of a human cell. This large-scale genetic network complements the DepMap gene co-essentiality network by capturing unique functional information, uncovering roles of previously uncharacterized genes, and identifying molecular determinants of cancer-cell-line-specific genetic dependencies. This study presents a general data-driven strategy for systematically exploring the roles of genes and their functional connections in human cell lines.
Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition
(Elsevier B. V., 2026-04-15) Reyes, José; Del Priore, Isabella; Chaikovsky, Andrea C.; Pasnuri, Nikhita; Elhossiny, Ahmed M.; Park, Jin; Weiler, Philipp; Krause, Tobias; Moorman, Andrew; Snopkowski, Catherine; Takizawa, Meril; Burdziak, Cassandra; Ratnayeke, Nalin; Masilionis, Ignas; Ho, Yu-Jui; Chaligné, Ronan; Romesser, Paul B.; Filliol, Aveline; Nawy, Tal; Morris, John P.; Zhao, Zhen; Pasca Di Magliano, Marina; Alonso Curbelo, Direna; Pe’er, Dana; Lowe, Scott W.
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.
Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation
(American Association for the Advancement of Science, 2026-04-03) Belloc Rocasalbas, Eulàlia; Calderone, Vittorio ; Naranjo Suárez, Salvador; Mateo Ramos, Lidia; Martín, Judit ; Malizia, Florencia; Sibilio, Annarita; Chanes Villar, Verónica; Ramírez Pedraza, Marta ; Delgado, M. Eugenia ; Drebber, Uta; Rheinwalt, Karl P. ; Klein, Sabine; Brol, Maximilian Joseph ; Schierwagen, Robert ; Trebicka, Jonel ; Aloy Calaf, Patrick; Fernandez, Mercedes ; Méndez de la Iglesia, Raúl
Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well characterized, the posttranscriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that similar to 70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3 ' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
Age-dependent mutational loads in human tRNA genes are tumor-specific and result in chimeric tRNA sequences that could disrupt the genetic code
(Cold Spring Harbor Laboratory Press, 2026-04-15) Murillo Recio, Marina; Salvadores Ferreiro, Marina; Vaquer Picó, Aina; Tsapanou, Lina; Torres, Adrian Gabriel; Supek, Fran; Ribas de Pouplana, Lluís
Transfer RNA genes (tDNAs) are essential genomic elements that safeguard translational fidelity. Using the Telomere-to-Telomere version of the human genome we have mapped the position of human tDNAs and analyzed their individual transcriptional activities. Then we have characterized, at single base resolution, the impact of somatic mutations in human tDNAs and its relationship to the transcriptional status of each gene. We confirm that tDNAs are hotspots for somatic mutagenesis, and show that they display mutational loads that are directly proportional to their transcription rates. Highly transcribed tDNAs in tumors or healthy tissues accumulate mutations at rates up to nine-fold higher than highly transcribed protein-coding genes. Mutational loads at tDNAs are tumor-specific, and increase with patient age. Mutations at structurally conserved tRNA positions appear to be under negative selection. Anticodon nucleotides crucial for decoding frequently acquire somatic mutations, readily generating chimeric tRNA species potentially capable of systematically introducing amino acid substitutions across the proteome. Our results reveal a previously unrecognized source of somatic heterogeneity in human cancer and aging tissues that may directly impact upon translation efficiency and fidelity, and cause cell-specific proteostasis degeneration
MAdPHOS, a P‑Stereogenic Aminodiphosphane Ligand withAdamantyl Groups: Synthesis, NH/PH Tautomerism, and Rhodiumand Nickel Complexes.
(American Chemical Society, 2025-01-29) Bellido, Marina; Solé Àvila, Helena; Sidro Inglés, Martí; Grabulosa, Arnald; Verdaguer i Espaulella, Xavier; Riera i Escalé, Antoni
A novel chiral ligand, named MAdPHOS, bearing aP-stereogenic phosphane and a diadamantyl phosphane linked by aNH bridge has been synthesized. This bulky, C1-symmetric, PNPligand has been prepared from enantiopure tert-butylmethylaminophosphane and was obtained as a crystalline solid. TheNH/PH tautomerism, air-stability, and σ-donor capacity ofMAdPHOS have been assessed herein. The free ligand has beenprepared, showing much higher stability, in the solid form, than itstert-butyl analogue MaxPHOS. Both rhodium and nickel CODcomplexes have been prepared. The Rh-MAdPHOS complex hasshown outstanding enantioselectivities in the asymmetric hydrogenationof enamides.
Exposomal determinants of non-genetic plasticity in tumor initiation
(Elsevier B.V., 2025-02-28) Carra, Davide; Maas, Silvana C.E.; Seoane, Jose A.; Alonso Curbelo, Direna
The classical view of cancer as a genetically driven disease has been challenged by recent findings of oncogenic mutations in phenotypically healthy tissues, refocusing attention on non-genetic mechanisms of tumor initiation. In this context, gene–environment interactions take the stage, with recent studies showing how they unleash and redirect cellular and tissue plasticity towards protumorigenic states in response to the exposome, the ensemble of environmental factors impinging on tissue homeostasis. We conceptualize tumor-initiating plasticity as a phenotype-transforming force acting at three levels: cell-intrinsic, focusing on mutant epithelial cells’ responses to environmental variation; reprogramming of non-neoplastic cells of the host, leading to protumor micro- and macroenvironments; and microbiome ecosystem dynamics. This perspective highlights cell, tissue, and organismal plasticity mechanisms underlying tumor initiation that are shaped by the exposome, and how their functional investigation may provide new opportunities to prevent, detect, and intercept cancer-promoting plasticity.
Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
(Springer, 2026-01-12) Núñez Rodríguez, Juan Carlos; Schikora Tamarit, Miquel Àngel; Gabaldón Esteban, Toni
The increasing prevalence of antifungal resistance represents a major clinical challenge. To explore potential new therapeutic avenues, we investigated fitness trade-offs associated with azole and echinocandin resistance in Nakaseomyces glabratus (syn. Candida glabrata), a priority yeast pathogen showing growing incidence of drug and multidrug resistance. For this, we comprehensively phenotyped a large collection (n = 77) of azole- and echinocandin-resistant strains to uncover resistance-associated stress sensitivity trade-offs. Our results show that increased stress sensitivity is a common trade-off of drug resistance in this species, with 98% of resistant strains exhibiting reduced fitness under at least one of six assayed stresses. Despite the diversity of genetic backgrounds and resistance mechanisms represented by our collection, we identified consistent trends in some resistance-associated vulnerabilities. Using multivariate modeling we uncovered complex genetic interactions underlying these trade-offs. As a proof of concept for therapeutic potential, we experimentally validated the inhibitory effects of targeting some fitness trade-offs. Cyclosporin A selectively inhibited anidulafungin-resistant strains, while NaCl effectively suppressed the emergence of fluconazole resistance. This study highlights the widespread occurrence of fitness costs associated with antifungal resistance and emphasizes their potential as a novel therapeutic strategy against this growing threat.
Experimental assessment of AI-based interactome mapping
(2026-04-04) Lambourne, Luke; Yadav, Anupama; Wang, Yang; Desbuleux, Alice; Kim, Dae-Kyum; Laval, Florent; Spirohn Fitzgerald, Kerstin; Cafarelli, Tiziana; Pons, Carles; Kovács, István A.; Jailkhani, Noor; Schlabach, Sadie; De Ridder, David; Luck, Katja; Botchkarev, Vladimir V.; Debnath, Olivia; Bian, Wenting; Shen, Yun; Yang, Zhipeng; Mee, Miles W.; Helmy, Mohamed; Jacob, Yves; Lemmens, Irma; Rolland, Thomas; McClain, Gregory G.; Coté, Atina G.; Gebbia, Marinella; Kishore, Nishka; Knapp, Jennifer J.; Mellor, Joseph C.; Memisoglu, Gonen; Reimand, Jüri; Tavernier, Jan; Cusick, Michael E.; Zhong, Quan; Aloy Calaf, Patrick; Hao, Tong; Charloteaux, Benoit; Roth, Frederick P.; Rivas, Javier de las; Falter Braun, Pascal; Hill, David E.; Calderwood, Michael A.; Twizere, Jean Claude; Vidal, Marc
Genotype-phenotype relationships are mediated through intricate networks of physical and functional interactions among macromolecules. Knowledge of the interactome is vital to understand and model genetics and cellular biology. Recent advances in accurately predicting tertiary protein structures using artificial intelligence (AI) approaches such as AlphaFold1 have revived the vision that the proteinprotein interactome might be fully predictable through computational modeling of quaternary structures. Here we present a comprehensive experimental framework to systematically assess the impact of AIdriven interactome predictions for yeast2 and human3. We find that the quality of high-confidence predictions is on par with established experimental approaches. However, in proteome-wide screening, the tested AI approaches underperform in the discovery of strictly novel protein-protein interactions (PPIs) compared to experimental reference interactome maps. In particular, the yeast interactome map describe here identifies >40-fold more novel PPIs than its AI counterpart. Strikingly, AlphaFold provides structural models for a substantial number of experimentally identified PPIs miss by the virtual screens. Our results suggest that, at this stage, the main contribution of AI predictions is to provide quaternary structure models for experimentally identified PPIs.
A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer
(American Association for Cancer Research, 2026-02-06) Centonze, Alessia; Roura Canalda, Adrià Jaume; Novillo Font, Meritxell; Giordano, Cristina; Hernando Momblona, Javier; Llanses Martínez, Montserrat; Prats Martínez, Paula; Sevillano Rosa, Marta; Cabot, Débora; Novell, Mireia; Pabst, Gabriel; Andersch, Florian; Cañellas Socias, Adrià; Zhang, Chong ; Giakoumakis, Nikolaos Nikiforos ; Sparks, Hugh; Dunsby, Chris; Colombelli, Julien; Fernández Barral, Asunción; Sancho Suils, Elena; Stephan-Otto Attolini, Camille; Muñoz, Alberto; Barbachano, Antonio; Martínez Quintanilla, Jordi; Palmer, Héctor G.; Zuber, Johannes; Blaj, Cristina; Sancho, Elena; Quintana, Elsa ; Cortina, Carme; Martí Renom, Marc A.; Batlle Gómez, Eduard
Inhibitors of the oncogene KRAS hold promise for treating metastatic colorectal cancer (mCRC). In this study, we show that a selective, covalent small-molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical colorectal cancer models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor prognosis-associated Emp1+ transcriptional state to a WNT-driven Lgr5+ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5+ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.Significance: We show that inhibition of oncogenic KRAS in preclinical models of advanced mCRC exerts a limited benefit, primarily due to the reversion of tumor cells to a stem cell-like state. Our findings highlight the context-dependent effects of oncogenic KRAS mutations and underscore cell plasticity as a therapeutic opportunity. See related commentary by Eng and Yilmaz et al., p. 201Significance: We show that inhibition of oncogenic KRAS in preclinical models of advanced mCRC exerts a limited benefit, primarily due to the reversion of tumor cells to a stem cell-like state. Our findings highlight the context-dependent effects of oncogenic KRAS mutations and underscore cell plasticity as a therapeutic opportunity. See related commentary by Eng and Yilmaz et al., p. 201
Oligomerization enables the selective targeting of an intrinsically disordered region by a small molecule
(Elsevier, 2026-02-27) Bielskutė, Stasė ; Mateos López, Borja; Awawdy, Muhammad ; Garcia Cabau, Carla; Niskanen, Henri ; Sánchez Zarzalejo, Carolina; Bracaglia, Lorenzo ; Pierattelli, Roberta ; Felli, Isabella C. ; Frigolé Vivas, Marta ; García Arroyo, Jesús; Riera Escale, Antoni; Hnisz, Denes ; Salvatella Giralt, Xavier
Intrinsically disordered regions (IDRs) in proteins are increasingly recognized as attractive targets for therapeutic intervention. A number of small molecules interacting with IDRs have been identified, but the lack of persistent secondary and tertiary structure of these regions has led to the prevailing view that they cannot be targeted selectively. Here, we show that a small molecule targeting an IDR evaluated in a clinical trial interacts selectively with an oligomeric form of its target, which is more structured than the monomer and is stabilized by interactions involving aromatic residues in partially α- helical regions. The interaction reshapes the conformational ensemble of the target, alters the biophysical properties of its phase- separated condensates in vitro, and attenuates RNA polymerase II recruitment in cells. Our findings provide mechanistic insights into how small molecules can selectively recognize IDRs.
Proteostasis failure and mitochondrial dysfunction contribute to chromosomal instability-induced microcephaly
(Springer Nature, 2026-03-12) Gonzalez Blanco, Amanda; Acuna Higaki, Adrian Ricardo; Boettger, David; Joy, Jery; Milán Kalbfleisch, Marco

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