Biology subjects

Dey, A.

Publications and source records attributed to Dey, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Preclinical Characterization of Hippo pathway inhibition: Insights from Pharmacological and Genetic Studies

The Hippo pathway is an evolutionarily conserved regulator of growth, regeneration, and organ homeostasis, and while its dysregulation is well established in cancer, the effects of inhibiting this pathway on normal tissues are less understood. Here we have systematically investigated the impact of Hippo pathway inhibition by comparing pharmacologic perturbation using a covalent small-molecule TEAD inhibitor (TEADi CMPD1, also known as GNE-8025) with genetic suppression of YAP/TAZ. We identified three key target organs that consistently emerged upon TEAD inhibition: the kidney, as well as the pancreas, and thymus. Across models, both perturbations led to comparable disease phenotypes in these organs, including tubular degeneration in the kidney, acinar atrophy in the pancreas, and lymphoid depletion in the thymus. However, the extent of damage was more pronounced in mice treated with the small-molecule inhibitor, highlighting potential dose and compound specific effects while remaining broadly consistent with the phenotypes observed upon genetic ablation of YAP/TAZ. This highlights the key role of evaluating both genetic and pharmacological perturbations to characterize the phenotypes and potential toxicities when modulating novel targets in oncology. To further investigate the mechanisms underlying pan-TEAD inhibition and kidney related adverse effects, we further characterized this class effect through a comprehensive transcriptomic analysis of the kidney to map the pathways involved in renal response. SignificanceUnderstanding on target toxicities is critical for the safe clinical development of TEAD inhibitors. Here, by integrating pharmacologic TEAD inhibition with genetic suppression by developing a mouse model that characterizes systemic, inducible knockdown of YAP/TAZ, we provide a systematic framework to define the Hippo pathway liabilities in vivo. We identify kidney, pancreas, and thymus as conserved target organs with concomitant phenotypes across both genetic and pharmacological methods, establishing these as pathway driven effects. Importantly, we uncover dose dependent and partially irreversible injury, particularly in kidney and pancreas, alongside mechanistic insight linking TEAD inhibition to aldosterone signaling disruption in kidney. These findings highlight the importance of strategies to identify monitorable, manageable adverse effect to guide clinical translation of TEAD targeting strategies.

cancer biology↗

bioRxiv2026

A Mecom—Cdk6 toggle switch governs hematopoietic stem-to-multipotent fate transitions via distinct multistable landscapes

Hematopoietic stem cells are required to regenerate the blood system throughout life. We previously discovered that transitions between quiescent stem and multipotent progenitor states are controlled by mutual inhibition between Mecom and Cdk6, with upstream regulation from the insulin-like growth factor (IGF) signaling pathway. To investigate the dynamics of exit from quiescence and the stem-to-multipotent cell state transition, we modeled the Mecom-Cdk6 regulatory network via coupled nonlinear differential equations. Bifurcation analysis revealed that the model permits tetrastability, with two stable intermediate states, suggesting that stem cell exit from quiescence proceeds via multiple fine-scale transitions. Perturbation of Mecom self-activation reorganized the multistable landscape, producing two IGF-dependent landscapes with distinct geometries. At high IGF, transitions proceeded only through an intermediate state, whereas at low IGF, a distinct landscape emerged permitting direct transitions between cell states. Stochastic simulations and minimum action path analysis showed that the multipotent attractor is deep at high IGF, whereas low IGF promotes a transition to quiescence by stabilizing the stem cell state. Simulated pharmacological intervention via CDK4/6 inhibitors destabilized the multipotent state and favored transitions towards a more stem-like quiescent state. Together, these results demonstrate how IGF signaling, Mecom self-activation, and Cdk6 inhibition jointly shape early stem cell fate decisions by dictating the accessible cell states on multistable landscapes and the transition paths that connect them.

Systems Biology↗

bioRxiv2026

Intra-nanoparticle Drug-protein Interactions Mediate Sequential Therapeutic Release

Controlled drug delivery systems have important implications in many therapeutic applications to improve patient health, but it remains challenging to deliver therapeutics to specific target sites while being released at controlled rates to minimize the off-target accumulation. Here, we report a drug (e.g., vancomycin)-modulating other drug release strategies in human serum albumin (HSA)-based nanoparticles (NPs) to achieve multiple drug encapsulation and controlled release of drugs. Without external stimuli but only with water, the release kinetics of drugs such as sulfasalazine and epidermal growth factor can be modulated by adding vancomycin. The mechanistic study suggests that the release kinetics are related to the secondary structure of albumin through the interactions between drugs and HSA. Our strategy achieved controlled drug delivery through modulating the secondary structure of albumin with a water-soluble drug as a modulator, which provides a promising way to simultaneously deliver multiple drugs while releasing in a predicted and sustained manner.

bioengineering↗

bioRxiv2026

Quantifying the Localization of Histological Staining Markers within the GI Epithelial Unit Axis: A Gastrointestinal Spatial Pathology Plugin for ImageJ

Histological analysis is crucial for understanding gastrointestinal (GI) tract homeostasis and disease pathophysiology. Various histological stains are commonly used in research settings for assessing development, disease pathogenesis, and therapeutic impacts. Specifically in the ordered architecture of the GI epithelium, current semi-quantitative analysis of histological staining relies heavily on manual scoring rubrics and often lacks robust spatial assessment. To address this gap, we developed an open-source ImageJ plugin, building on a closed-source predecessor, aimed at analyzing the spatial localization pattern of user-defined points-of-interest, such as positively stained cells, along the GI epithelial units. The plugin, developed using ImageJ 1.53.0 and Java programming language in Eclipse, interfaces with ImageJ and leverages Java libraries for data processing. The workflow involves uploading a microscopy image of the GI tissue of interest, determining base and top orientation landmarks of the GI epithelial units through manual identification, and annotating point-of-interest coordinates using ImageJ. The output includes centroid coordinates for each point-of-interest, the absolute distances of the points from the base and top landmarks, and the normalized distances of the points relative to the total height of the GI unit. The plugin generates histograms for displaying average point-of-interest distances along the GI unit axis. This information facilitates quantification of total points-of interest counts, analysis of height localization within the GI unit, and determination of average GI unit heights. The plugin serves as a crucial tool for robustly assessing various biological mechanisms within the GI tract, including EdU localization, migration distances, changes in cell type localization, and identification of new expression patterns along the GI unit axis. Overall, this open-source ImageJ plugin provides a semi-automated, user-friendly solution for leveraging important insights into spatial localization of tissue histology expression patterns within the GI structured architecture, with streamlined post-processing pipelines for robust large-scale analysis.

bioengineering↗

bioRxiv2026

Pan-Viral Conformational Landscapes of Frameshifting Elements Reveal Length-Dependent Plasticity and Antisense-Driven Structural Reprogramming

Programmed ribosomal frameshifting (PRF) is an essential strategy used by many RNA viruses to expand their coding capacity within compact genomes. This process is governed by frameshifting elements (FSEs), specialized RNA structures that regulate translation through dynamic secondary and tertiary conformations. While the structural adaptability of the SARS-CoV-2 FSE has been extensively characterized, the conformational landscapes of FSEs across other pathogenic viruses remain poorly understood. Here, we present a comparative structural analysis of FSEs from Japanese Encephalitis Virus (JEV), West Nile Virus (WNV), Hepatitis C Virus (HCV), and Human Immunodeficiency Virus (HIV) using integrative computational modeling and molecular simulations. Our analysis reveals previously uncharacterized, virus-specific conformational ensembles, alongside a conserved core architecture that exhibits pronounced length-dependent structural plasticity. Extension of flanking sequences induces substantial conformational rearrangements, highlighting the role of sequence context in shaping FSE topology and potentially modulating PRF efficiency. Importantly, we demonstrate that antisense oligonucleotide (ASO) binding can reprogram FSE architectures, disrupting native structural motifs and stabilizing alternative conformations with altered thermodynamic stability. Collectively, these findings establish viral FSEs as dynamic RNA ensembles governed by sequence context and external interactions, and position ASO-mediated structural perturbation as a promising strategy for modulating frameshifting and viral gene expression.

bioinformatics↗

bioRxiv2026

SRSA-VAE: Self-Attention-Based Feature Learning for Single-Cell Multimodal Clustering

Clustering plays a critical role in the analysis of single-cell omics data for identifying cellular heterogeneity and uncovering biological mechanisms. However, the high dimensionality, sparsity, and multimodal nature of single-cell datasets such as single-cell RNA sequencing (scRNA-seq) and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) pose significant challenges for effective feature learning and representation learning. Traditional dimensionality reduction methods often rely on linear transformations and fail to capture complex nonlinear relationships between gene and protein expression profiles. In this work, we propose SRSA-VAE, a scalable variational autoencoder framework that integrates a residual self-attention encoder for context-aware feature learning and multimodal representation learning. The proposed model dynamically contextualizes gene and protein representations through a self-attention mechanism, enabling the encoder to capture inter-cell relationships and emphasize biologically informative signals. A scalable residual connection further stabilizes training and preserves essential input information during latent representation learning. We evaluate SRSA-VAE on five large-scale publicly available single-cell datasets, including both scRNA-seq and CITE-seq data, and compare its performance with established deep generative models. Experimental results demonstrate that SRSA-VAE consistently outperforms existing methods in Adjusted Rand Index (ARI) across benchmark datasets, with particularly strong gains on complex immune cell populations. Ablation studies further confirm the importance of the self-attention mechanism and residual connection in enhancing model stability and clustering accuracy. The proposed model offers a generalizable, robust, and scalable solution for single-cell clustering tasks. Code Repositoryhttps://github.com/rangan2510/srsa-vae

bioinformatics↗

bioRxiv2026

Loop Extrusion Reversal by Condensin Motor is Mediated by Catch Bonds

Structural Maintenance Complexes (SMC) are energy consuming motors that are important in folding the genome by loop extrusion (LE) in all stages of the cell cycle. Single molecule magnetic tweezer pulling experiments have revealed that condensin, a member of the SMC family involved in mitosis, takes occasional backward steps, thus coughing up the gains in the length of the extruded loop. To reveal the mechanism of the forward and backward steps simultaneously, we developed a theory using the stochastic kinetic model and the scrunching mechanism for LE. The calculations quantitatively account for the measured force-dependent step size and dwell time distributions in both the directions. By postulating the existence of an intermediate state in the ATP-driven cycle that is poised to take a forward or a backward step, we predict that its lifetime increases as the external mechanical force increases till a critical value and subsequently decreases at higher forces. The surprising finding of lifetime increase in an active motor, at sub-piconewton forces, is the characteristic of catch bonds, known in force-induced rupture of several passive protein complexes. The identification of catch bond-like states in condensin not only expands our understanding of LE but also highlights the significance of mechanical forces in regulating genome organization.

biophysics↗

bioRxiv2026

M-CSF drives alveolar macrophage plasticity during development and cytomegalovirus infection

Alveolar macrophages (AM), the most frequent resident immune cells of the lung, are at the first line of defence against respiratory pathogens and instruct structural lung cells, e.g. in tissue repair. They are long-lived and receive their terminal phenotypic imprint through signals originating from the unique location at the tissue-air interface, as well as through cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-{beta} (TGF-{beta}). However, the regulatory mechanisms governing their phenotypic plasticity, which is conceptually critical for their positioning and differentiation in early life and for their functional adaptation during infection, remain poorly defined. Here we explored respiratory tract infection with cytomegalovirus (CMV), which is closely linked to mammalian immune evolution. Complementary host-pathogen fate-mapping strategies revealed AM to constitute the bottleneck for efficient mouse (M)CMV infection. MCMV infection induced macrophage colony-stimulating factor (M-CSF) in the alveolar space, and culturing of AM in M-CSF led to a profound remodelling of morphology, immunophenotype, and transcriptional identity, e.g. it increased the expression of interferon-stimulated genes (ISG), which modulated susceptibility to infection. Notably, already at baseline recently differentiated neonatal AM across species retained an M-CSF-associated transcriptional program. This was linked to reduced permissiveness to respiratory MCMV infection in vivo. Overall, our findings identify the role of M-CSF-dependent signalling in conferring plasticity to AM, when it is most needed, particularly during early-life establishment and in response to viral infection.

immunology↗

bioRxiv2026

Altered chromatin accessibility and nucleosome positioning landscape upon HDAC and LSD1 inhibition in cancer cell

Epigenetic enzymes, writers, readers and erasers regulate chromatin landscapes and participate in tumor heterogeneity. While therapeutic targeting of these enzymes has shown clinical promise, the comparative efficacy of mono-versus dual-inhibitor strategies remain unclear. Here, we introduce a multi-modal platform that uses NicE-viewSeq and integrates automated deep learning based spatially resolved chromatin accessibility profiling with high-throughput sequencing following epigenetic inhibitor application. Accessible chromatin landscapes were altered along with nucleosome positioning following inhibition of either LSD1 or HDACs alone, or both together. Coordinated modulation of histone marks and the CoREST complex on chromatin was observed across inhibitory conditions. Transcription factor binding analysis identified three predominant families, ETS, RUNT, and bZIP with enhanced chromatin association upon treatments. Mechanistically, a CoREST-RUNX regulatory axis was uncovered wherein JunB, a member of bZIP family displaces CoREST-RUNX at differentially accessible regions, triggering apoptotic pathways. Therefore, JunB-mediated mechanism reveals a convergent therapeutic vulnerability, offering new avenues for optimizing different combinatorial epigenetic therapy in cancer.

genetics↗

bioRxiv2026

Constructing a single-objective oblique plane microscope (OPM) for fast, multi-colour, high-resolution volumetric fluorescence imaging

Oblique plane microscopy (OPM) is a light sheet microscopy technique that uses a single high numerical aperture (NA) objective for both illuminating the sample and collecting emission fluorescence from a tilted plane within the specimen. OPM has become indispensable in biological and biomedical research, providing rapid, high-resolution volumetric fluorescence imaging of live cells and tissues while minimising phototoxicity and photobleaching. It also overcomes the sample mounting challenges associated with conventional light sheet microscopes that require two orthogonally placed objectives. However, the application of OPM has been limited by the complex design and the intricate optical alignment and characterisation needed, particularly with the remote-refocusing system (RFS) in the emission path. This protocol offers a detailed, step-by-step guide for constructing an OPM setup using commercially available components and for characterising its performance to ensure optimal imaging quality. We aim to deliver the unique merits of OPM to researchers in life science and medicine, enabling them to visualise the spatiotemporal organisation of key biomolecules, structures, and cells in 3D at high resolutions.

biophysics↗

bioRxiv2026

Efficient task generalization and humanlike face perception in models that learn to discriminate face geometry

Artificial deep neural networks (DNNs) can excel at face recognition from 2D photographs where both shape and appearance cues abound; however, DNNs have rarely been challenged to recognize faces strictly based on face geometry. Here, we show that DNNs, even those fine-tuned on face photographs, had almost no generalization performance to a new geometry-based face task, while in the opposite direction, networks fine-tuned only on geometrically defined, textureless faces readily generalized to textured faces. To learn geometry in a more practical setting with colored and textured faces, we trained discrimination on face emotion in addition to face identity, which resulted in less texture bias and generalized well across face tasks. Learning in this way from just four individuals and their expressions generalized to unseen individuals, even exceeding standard models which are trained on classifying hundreds of face identities. Compared to standard models, emotion and identity trained models developed more humanlike errors in the identities or emotions that they confused. This novel method learns in a humanlike manner using only a few individuals but enriched with expressions that widely vary face geometry - similar to early human experience during child-parent interactions. Thus, this bioinspired work has broad implications for how moving toward humanlike learning of geometry in artificial vision can be both highly sample efficient and highly performing.

neuroscience↗

bioRxiv2026

ESMDisPred: A Structure-Aware CNN-Transformer Architecture for Intrinsically Disordered Protein Prediction

Intrinsically disordered proteins (IDPs) lack stable three-dimensional structures, yet play vital roles in key biological processes, including signaling, transcription regulation, and molecular scaffolding. Their structural flexibility presents significant challenges for experimental characterization and contributes to diseases such as cancer and neurodegenerative disorders. Accurate computational prediction of IDPs is important for advancing research and drug discovery, structural biology, and protein engineering. In this study, we introduce ESMDisPred, a novel structure-aware disorder predictor that builds on the representational power of Evolutionary Scale Modeling-2 (ESM2) protein language models. ESMDisPred integrates sequence embeddings with structural information from the Protein Data Bank (PDB) to deliver state-of-the-art prediction accuracy. Model performance is further enhanced through feature engineering strategies, including terminal residue encoding, statistical summarization, and sliding-window analysis. To capture both local sequence motifs and long-range dependencies, we designed a hybrid CNN-Transformer architecture that balances convolutional efficiency with the representational power of self-attention. On CAID3 benchmarks, our latest model achieves ROC-AUC 0.895, AP 0.778, and a max F1 of 0.759, outperforming recent methods. Our results highlight the importance of integrating protein language model embeddings with explicit structural information for improved disorder prediction.

bioinformatics↗

bioRxiv2025

Lymphotoxin-driven cancer cell eradication by tumoricidal CD8+ tumor-infiltrating lymphocytes

Tumor-infiltrating lymphocyte (TIL) therapy is FDA-approved for patients with treatment-resistant advanced melanoma, but the TIL subpopulations critical for tumor eradication remains incompletely understood. Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8+ TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin {beta} receptor (LT{beta}R) and interferon (IFN) sensing pathways were nominated as key determinants of TIL-mediated cancer cell killing from a whole-genome, loss-of-function CRISPR screen. Validation studies confirmed that dual LT{beta}R and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8+ TIL express high lymphotoxin {beta} (LTB) and upregulate lymphotoxin (LTA) upon coculture with cancer cells. Leveraging paired scRNA-seq and scTCR-seq data, we confirmed that enrichment of LTB+CD8+ T cells is associated with clinical response to TIL, and that LTB+CD8+ TIL are expanded from putative neoantigen-reactive, LTBlo CD8+ T cells in resected tumors. SignificanceWe have uncovered a previously unrecognized mechanism of TIL-mediated tumor eradication, providing mechanistic insights into the role of LTBR/IFN signaling in TIL-mediated cancer cell killing, and potentially offering insights into novel strategies to isolate, enrich, and expand tumoricidal TIL or augment specific TIL functions to enhance tumor control.

cancer biology↗

bioRxiv2025

Amphibious Transitions Drive Lineage-Specific Diversification of Olfactory Receptors in Vertebrates

Olfactory receptors (ORs), which mediate chemical detection in vertebrates, constitute a highly dynamic and ecologically responsive gene family. While OR evolution has been well studied in fully terrestrial and aquatic lineages, its dynamics in amphibious vertebrates remain less explored. Species that occupy both aquatic and terrestrial habitats span a broad phylogenetic and ecological range--from amphibians to freshwater-dwelling mammals, semi-aquatic reptiles, and shoreline birds--and are subject to the functional demands of odour detection across two chemically disparate milieus. Here, we analysed OR gene repertoires across 230 vertebrate genomes, including 138 amphibious species. Our results show that OR repertoire expansion is not a uniform feature of terrestrial adaptation but is most pronounced in amphibious lineages, particularly those inhabiting freshwater systems, where chemically variable environments likely impose stronger selective pressures on olfaction. These expansions are primarily driven by lineage-specific expansions and correlate with ecologies that require sensing a wide range of chemical cues. While amphibious marine taxa possess larger OR repertoires than their fully marine relatives, they consistently exhibit fewer ORs than freshwater amphibious vertebrates. More broadly, species that rely on other sensory modalities--such as echolocation, electroreception, or vision--tend to exhibit reduced OR repertoires. Despite this diversity, several amphibious and terrestrial species within the same clade retain a small subset of shared OR genes, reflecting the retention of conserved OR orthologs--potentially those tuned to airborne odorants--across habitat transitions. However, overlap across clades is minimal, reflecting independent evolutionary responses to similar ecological pressures. Overall, our findings highlight amphibious lifestyles as key inflection points in vertebrate olfactory evolution--driving both OR repertoire expansion and divergence through the interplay of habitat complexity, sensory trade-offs, and lineage-specific constraints.

evolutionary biology↗

bioRxiv2025

Genome of the Predatory Volute Melo melo Provides Insights into Adaptive Gene Family Diversification in a Basal Neogastropod Lineage

Neogastropods represent one of the most diverse and ecologically specialized lineages of marine mollusks, yet many of their early-diverging families remain genomically underexplored. Here, we present the first high-contiguity genome of a volutid species, the tropical predatory snail Melo melo, assembled using PacBio HiFi long reads. The final assembly spans 2.29 Gb with high contiguity (N50: 18.6 Mb) and completeness (BUSCO: 92.4%). Phylogenomic analyses place M. melo as an early-branching neogastropod lineage, supporting the basal position of Volutidae within the order. Comparative genomic analyses reveal expansions of gene families associated with digestion and nutrient metabolism (e.g., metallopeptidases), neurotoxicity (conotoxin-like genes), neurotransmission (ion channels), detoxification (cytochrome P450s and ABC transporters), and innate immunity (C1q and LRR-containing proteins), among others. These expansions are consistent with M. melos predatory behavior and adaptation to sediment-rich benthic habitats. Notably, M. melo lacks nacre-related genes but retains several biomineralization-related gene families previously implicated in shell and pearl formation, offering a genomic basis for investigating its distinctive non-nacreous phenotype. Orthology and CAFE analyses further reveal both conserved and lineage-specific dynamics of gene families across the analyzed gastropods. This study fills a key phylogenetic gap in molluscan genomics and establishes Melo melo as a valuable model for understanding the genomic basis of ecological adaptation and trait evolution in basal neogastropods.

genomics↗

bioRxiv2025

Deficiency in POLE exonuclease causes synthetic lethality in highly aneuploid cancer cells

Aneuploidy is a hallmark of cancer and is associated with drug resistance and poor clinical outcomes across diverse cancer types. However, no therapies have been clinically established to target highly aneuploid tumors. By analyzing a real-world dataset comprising nearly half a million tumor samples subjected to comprehensive genomic profiling, we identified a striking mutual exclusivity between POLE exonuclease domain mutations and high aneuploidy burden. This observation was independently validated using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Probabilistic modeling revealed that the elevated quantity and unique spectrum of mutations induced by POLE exonuclease deficiency increase the likelihood of inactivating essential genes on chromosome arms harboring losses, leading to a synthetic lethal phenotype in highly aneuploid cells. Functional experiments demonstrated that POLE exonuclease activity is essential for the viability of highly aneuploid cancer cell lines but is dispensable in diploid cells. These findings suggest that selective inhibition of POLE exonuclease may represent a promising therapeutic strategy for targeting highly aneuploid tumors.

cancer biology↗

bioRxiv2025

Actin waves guide an outward movement of microclusters in the lymphocyte immunological synapse

The lymphocyte immune response begins with antigen recognition on antigen-presenting cells, leading to the formation of the immunological synapse--a specialized interface for biochemical and biophysical exchange. At the synapse, most antigen-engaged receptor microclusters move inward toward the central supramolecular activation cluster (cSMAC) via retrograde F-actin flow, eventually clearing from the cell surface. This retrograde movement and receptor downregulation maintain antigen receptor homeostasis, critical for adaptive immunity, though its regulation remains unclear. Using live T cells, we identified a significant pool of antigen-engaged microclusters moving anterogradely toward the cell periphery, rather than the cSMAC. This movement was driven by actin waves propagating outward and coupling to microclusters through the Wiskott-Aldrich Syndrome Protein. These findings reveal a previously unrecognized mode of actin dynamics--anterograde actin waves--that co-exist with retrograde flow and direct microclusters away from the downregulation zone. This dual actin behavior underscores the complex cytoskeletal mechanisms T cells employ to regulate receptor distribution and maintain signaling homeostasis during immune activation.

immunology↗

bioRxiv2025

YAP signaling promotes resistance to MEK and AKT inhibition in NF1-related MPNSTs

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by loss of function of the neurofibromin protein. Malignant peripheral nerve sheath tumors (MPNSTs) are a rare and deadly sarcoma with few therapeutic options that are the leading cause of death for patients with NF1. To date, no targeted therapies have been approved for MPNST treatment, highlighting the need for an understanding of adaptive signaling mechanisms that drive resistance. We developed a preclinical model of drug resistance using a cross-over drug holiday design and evaluated patterns of response and resistance to MEK and AKT inhibitors, two pathways that are dysregulated by loss of neurofibromin. We show that the mTOR and YAP/TEAD pathways are activated by MEK inhibitor exposure, yet blockade of these pathways in resistant MPNST PDX models does not significantly reduce tumor growth, despite strong in vitro synergy between trametinib and the novel TEAD inhibitor, GNE-7883. Using spatial transcriptomics, we uncovered phenotypic inertia as a key mechanism of drug resistance in MPNST, in addition to signaling plasticity. Further, we found that resistance is mediated by sustained ERK, YAP, and MYC driven transcriptional programs. In the future, preclinical studies should focus on addressing intratumoral heterogeneity and how it evolves over time.

cancer biology↗