Biology subjects

Arora, S.

Publications and source records attributed to Arora, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, the most common intracranial tumor, though mostly benign can be recurrent and fatal. WHO grading does not always identify high risk meningioma and better characterizations of their aggressive biology is needed. To approach this problem, we combined 13 bulk RNA-Seq datasets to create a dimension-reduced reference landscape of 1298 meningiomas. Clinical and genomic metadata effectively correlated with landscape regions which led to the identification of meningioma subtypes with specific biological signatures. Time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape where nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcome. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

cancer biology↗

bioRxiv2023

Differential substrate specificity of ERK, JNK, and p38 MAP kinases toward Connexin 43

Phosphorylation of connexin 43 (Cx43) is an important regulatory mechanism of gap junction (GJ) function. Cx43 is modified by several kinases on over 15 sites within its [~]140 amino acid-long C-terminus (CT). Phosphorylation of Cx43CT on S255, S262, S279, and S282 by ERK has been widely documented in several cell lines, by many investigators. Phosphorylation of these sites by JNK and p38, on the other hand, is not well-established. Indeed, ERK is a kinase activated by growth factors and is upregulated in diseases, such as cancer. JNK and p38, however, have a largely tumor-suppressive function due to their stress-activated and apoptotic role. We investigated substrate specificity of all three MAPKs toward Cx43CT, first by using purified proteins, and then in two cell lines (MDCK - non-cancerous, epithelial cells and porcine PAECs - pulmonary artery endothelial cells). Cx43 phosphorylation was monitored through gel-shift assays on an SDS-PAGE, immunodetection with phospho-Cx43 antibodies, and LC-MS/MS phosphoproteomic analyses. Our results demonstrate that p38 and JNK specificity differ from each other and from ERK. JNK has a strong preference for S255, S262, and S279, while p38 readily phosphorylates S262, S279, and S282. While we confirmed that ERK can phosphorylate all four serines (255, 262, 279, and 282), we also identified T290 as a novel ERK phosphorylation site. In addition, we assessed Cx43 GJ function upon activation or inhibition of each MAPK in PAECs. This work underscores the importance of delineating the effects of ERK, JNK, and p38 signaling on Cx43 and GJ function.

biochemistry↗

bioRxiv2023

Joint sequence & chromatin neural networks characterize the differential abilities of Forkhead transcription factors to engage inaccessible chromatin

The DNA-binding activities of transcription factors (TFs) are influenced by both intrinsic sequence preferences and extrinsic interactions with cell-specific chromatin landscapes and other regulatory proteins. Disentangling the roles of these binding determinants remains challenging. For example, the FoxA subfamily of Forkhead domain (Fox) TFs are known pioneer factors that can bind to relatively inaccessible sites during development. Yet FoxA TF binding also varies across cell types, pointing to a combination of intrinsic and extrinsic forces guiding their binding. While other Forkhead domain TFs are often assumed to have pioneering abilities, how sequence and chromatin features influence the binding of related Fox TFs has not been systematically characterized. Here, we present a principled approach to compare the relative contributions of intrinsic DNA sequence preference and cell-specific chromatin environments to a TFs DNA-binding activities. We apply our approach to investigate how a selection of Fox TFs (FoxA1, FoxC1, FoxG1, FoxL2, and FoxP3) vary in their binding specificity. We over-express the selected Fox TFs in mouse embryonic stem cells, which offer a platform to contrast each TFs binding activity within the same preexisting chromatin background. By applying a convolutional neural network to interpret the Fox TF binding patterns, we evaluate how sequence and preexisting chromatin features jointly contribute to induced TF binding. We demonstrate that Fox TFs bind different DNA targets, and drive differential gene expression patterns, even when induced in identical chromatin settings. Despite the association between Forkhead domains and pioneering activities, the selected Fox TFs display a wide range of affinities for preexiting chromatin states. Using sequence and chromatin feature attribution techniques to interpret the neural network predictions, we show that differential sequence preferences combined with differential abilities to engage relatively inaccessible chromatin together explain Fox TF binding patterns at individual sites and genome-wide.

genomics↗

bioRxiv2023

The wheat powdery mildew resistance gene Pm4 also confers resistance to wheat blast

Wheat blast, caused by the fungus Magnaporthe oryzae, threatens global cereal production since its emergence in Brazil in 1985 and recently spread to Bangladesh and Zambia. Here we demonstrate that the AVR-Rmg8 effector, common in wheat-infecting isolates, is recognised by the gene Pm4, previously shown to confer resistance to specific races of Blumeria graminis f.sp. tritici, the cause of powdery mildew of wheat. We show that Pm4 alleles differ in their recognition of different AVR-Rmg8 alleles, and some confer resistance only in seedling leaves but not spikes making it important to select for those alleles that function in both tissues. This study has identified a gene recognising an important virulence factor present in wheat blast isolates in Bangladesh and Zambia and represents an important first step towards developing durably resistant wheat cultivars for these regions.

plant biology↗

bioRxiv2023

Liquid-liquid phase separation and aggregation of a globular folded protein SUMO1

Many studies in recent years have investigated the phenomenon of liquid-liquid phase separation (LLPS) in proteins. LLPS is reported in intrinsically disordered proteins (IDPs) or in proteins with intrinsically disordered regions (IDRs) lacking a well-defined three-dimensional structure. However, the occurrence of LLPS in folded proteins, that lacks IDRs is not widely known. It is generally assumed that the compact structure and limited flexibility of folded proteins hinder their ability to establish weak and dynamic interactions crucial for LLPS. Contrary to the prevailing understanding, we present direct evidence of rapid phase separation of a globular protein, SUMO1, occurring under crowded conditions at physiological pH and room temperature. The protein molecules in the liquid droplets undergo conformational changes with time, monitored by intrinsic tryptophan fluorescence. We also demonstrate the phase transition of SUMO1 droplets from liquid to solid state with maturation, ultimately leading to aggregation. The SUMO1 aggregates contain a significant amount of beta-sheet structure but have amorphous morphology, probed by several spectroscopic techniques (Thioflavin T fluorescence, Raman Spectroscopy, and TEM). Our findings provide insights into the behaviour of SUMO1 protein in crowded environment, albeit, the underlying mechanism is not well understood and may differ from those of IDPs. Furthermore, SUMO1 protein is known to colocalize in inclusion bodies of IDPs, and therefore, LLPS of SUMO1 may have important biological implications in neurodegenerative diseases.

biophysics↗

bioRxiv2023

Artificial Intelligence uncovers Evolutionarily Conserved Intracellular Allosteric Modulators of GPCR-Gα interface.

Endogenous intracellular allosteric modulators of GPCRs remain largely unexplored, with limited binding and phenotype data available. This gap arises from the lack of robust computational methods for unbiased cavity identification, cavity-specific ligand design, synthesis, and validation across GPCR topology. Here, we developed Gcoupler, an AI-driven generalized computational toolkit that leverages an integrative approach combining de novo ligand design, statistical methods, Graph Neural Networks, and Bioactivity-based ligand prioritization for rationally predicting high-affinity ligands. Using Gcoupler, we interrogated intracellular metabolites that target and regulate the GPCR-G interface (Ste2p-Gpa1p), affecting pheromone-induced programmed cell death in yeast. Our computational analysis, complemented by experimental validations, including genetic screening, multi-omics, site-directed mutagenesis, biochemical assays, and physiological readouts, identified endogenous hydrophobic metabolites, notably sterols, as direct intracellular allosteric modulators of Ste2p. Molecular simulations coupled with biochemical signaling assessment in site-directed Ste2p mutants further confirmed that metabolites binding to GPCR-G obstruct downstream signaling, possibly via a cohesive effect. Finally, by utilizing isoproterenol-induced, GPCR-mediated human and neonatal rat cardiac hypertrophy models, we observed that elevated metabolite levels attenuate hypertrophic response, reinforcing the evolutionary relevance of this mechanism.

bioinformatics↗

bioRxiv2023

Functional genomic analysis of adult and pediatric brain tumor isolates

BackgroundAdult and pediatric tumors display stark differences in their mutation spectra and chromosome alterations. Here, we attempted to identify common and unique gene dependencies and their associated biomarkers among adult and pediatric tumor isolates using functional genetic lethal screens and computational modeling. MethodsWe performed CRISRP-Cas9 lethality screens in two adult glioblastoma (GBM) tumor isolates and five pediatric brain tumor isolates representing atypical teratoid rhabdoid tumors (ATRT), diffuse intrinsic pontine glioma, GBM, and medulloblastoma. We then integrated the screen results with machine learning-based gene-dependency models generated from data from >900 cancer cell lines. ResultsWe found that >50% of candidate dependencies of 280 identified were shared between adult GBM tumors and individual pediatric tumor isolates. 68% of screen hits were found as nodes in our network models, along with shared and tumor-specific predictors of gene dependencies. We investigated network predictors associated with ADAR, EFR3A, FGFR1 (pediatric-specific), and SMARCC2 (ATRT-specific) gene dependency among our tumor isolates. ConclusionsThe results suggest that, despite harboring disparate genomic signatures, adult and pediatric tumor isolates share a preponderance of genetic dependences. Further, combining data from primary brain tumor lethality screens with large cancer cell line datasets produced valuable insights into biomarkers of gene dependency, even for rare cancers. Importance of the StudyOur results demonstrate that large cancer cell lines data sets can be computationally mined to identify known and novel gene dependency relationships in adult and pediatric human brain tumor isolates. Gene dependency networks and lethality screen results represent a key resource for neuro-oncology and cancer research communities. We also highlight some of the challenges and limitations of this approach.

cancer biology↗

bioRxiv2023

An RNA seq-based reference landscape of human normal and neoplastic brain

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

bioinformatics↗

bioRxiv2022

Co-occurring mutations in the POLE exonuclease and non-exonuclease domains define a unique subset of highly mutagenic tumors.

Somatic POLE mutations in the exonuclease domain (ExoD) are prevalent in colorectal cancer (CRC), endometrial cancer (EC), and others and typically lead to dramatically increased tumor mutation burden (TMB). To understand whether non-ExoD mutations also play a role in mutagenesis, we assessed TMB in 447/14541 POLE-mutated CRCs, ECs, and ovarian cancers (OC) based on classification TMB-High (TMB-H) or TMB-Low (TMB-L). TMB-H tumors were segregated as POLE ExoD driver, POLE ExoD driver plus POLE Variant, and POLE Variant TMB-H. Intriguingly, TMB was highest in tumors bearing POLE ExoD driver plus POLE Variant (p<0.001 in CRC and EC, p<0.05 in OC). Integrated analysis of AlphaFold2-modeled POLE models and quantitative estimate of stability indicated that multiple variants had significant impact on functionality. These data indicate that co-occurring POLE variants categorize a unique subset of POLE-driven tumors defined by ultra-high TMB, which has implications for abundance of tumor neoantigens, therapeutic response, and patient outcomes. SignificanceSomatic POLE ExoD driver mutations cause proofreading deficiency that induces high tumor mutation burden (TMB). This study defines a novel modifier role for non-ExoD mutations in POLE ExoD-driven tumors, associated with ultra-high TMB. These data may inform acquisition of tumor neoantigens, tumor classification, therapeutic response, and patient outcomes.

cancer biology↗

bioRxiv2022

FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation, and lethality in glioblastoma and other cancers

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also essential in [~]15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest, and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42s cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42s substrate recognition and targeting by SCF ubiquitin ligase complex. However, none of FBXO42s previously proposed targets, including ING4, p53, and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 activity suppresses the accumulation of one or more proteins that perturb chromosome-microtubule dynamics in cancer cells, which, in turn, leads to induction of the SAC and cell death.

cancer biology↗

bioRxiv2022

MOLECULAR INSIGHTS INTO BINDING BEHAVIOUR OF LAMOTRIGINE WITH INITIATION FACTOR 2 PROTEIN: AN INTEGRATED COMPUTATIONAL STUDIES

CONSPECTUSO_ST_ABSAimsC_ST_ABSThe ribosomal protein (r-protein) of bacteria is composed of 2.6 MDa ribonucleoproteins of the 30S and 50S subunits, which are essential elements for protein translation. The translational initiation step is an intensive regulated multi-step reaction in protein biosynthesis. During bacterial protein synthesis, the correct reading frame of the mRNA defines when the initiator fMet-tRNAiMet binds to the start codon AUG at the P-site of the 30S subunit. The formation of the P-site of the 30S subunit initiation complex (30S-IC) is governed by three ubiquitous initiation factors (IFs) such as IF1, IF2, and IF3. IF2 protein is an essential player that plays during the last stage of the initiation process. Earlier, Stokes and his co-workers studied chemicals probes using 30K diverse drugs that induced cold-sensitive growth inhibition in the bacterium. The assay studies revealed, Lamotrigine (LTG) effectively binds at domain II of IF2 protein. In our research, we took an attempt in identifying promising active residues that could responsible for anti-bacterial bioactivity with help of computational studies. Computational MethodsIn the present study, initially, we performed C- backbone alignment with the retrieved IF2 chain from AlphaFold. Further, we utilized SiteMap and CastP for the identification of plausible active binding sites. Further, we bound LTG with the designated domain(s) of IF2 protein and studied its binding affinity potential with help of adaptive molecular dynamics simulations at atomic levels using Desmond. Key FindingsOur research findings have shown accurate results and we could able to prove the assertion in contrast with the findings of Stokes and his co-workers where the LTG bind at domain II of IF2 protein. The key interacting residue Glu179 was revealed to have strong hydrogen bonding contacts with LTG at the sub-nanomolar range. In addition, we predicted the alternative promising site I Further, we gained in-depth analysis for studying multiple sites, to understand the synergism inhibitory activity. Promisingly, LTG could be able to bound with at Site 1 showing better affinity over the proposed domain II and other predicted sites. The adaptive molecular dynamics studies confirmed the promising active residues SignificanceThe binding site predictions approach provides an insight for further development of anti-bacterial therapeutics that might helpful for bacteria disease management and exhibiting inhibitory activity against various strains.

bioinformatics↗

bioRxiv2022

Expression of YAP1-MAML2 and constitutively active YAP1 drive the formation of meningioma-like tumors in mice that resemble NF2-mutant meningiomas

YAP1 is a transcriptional co-activator regulated by the Hippo Signaling Pathway, including NF2. Meningiomas are the most common primary brain tumors, a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 copy, implicating oncogenic YAP activity in these tumors. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2-wild type meningiomas. Here, we show that human YAP1-MAML2-positive meningiomas resemble NF2-mutant meningiomas by global and YAP-related gene expression signatures. We then show that expression of YAP1-MAML2 in mice induces tumors that resemble human YAP1 fusion-positive and NF2-mutant meningiomas by gene expression. We demonstrate that YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Treatment with YAP-TEAD inhibitors is sufficient to inhibit the viability of YAP1-MAML2-driven mouse tumors ex vivo. Finally, we show that expression of constitutively active YAP1 (S127/397A-YAP1) is sufficient to induce similar tumors suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a causal oncogenic driver and highlight TEAD-dependent YAP activity as an oncogenic driver in YAP1-MAML2-fusion meningioma as well as NF2-mutant meningioma in general.

cancer biology↗

bioRxiv2022

Antibodies to Coagulase of Staphylococcus aureus crossreact to Efb and reveal different binding of shared Fibrinogen Binding repeats

Staphylococcus aureus pathology is caused by a plethora of virulence factors able to combat multiple host defence mechanisms. Fibrinogen (Fg), a critical component in the host coagulation cascade, plays an important role in the pathogenesis of this bacterium, as it is the target of multiple staphylococcal virulence proteins. Amongst its secreted virulence factors, Coagulase (Coa) and Extracellular fibrinogen-binding protein (Efb) share common Fg binding motives and have been described to form a Fg shield around staphylococcal cells, thereby allowing efficient bacterial spreading, phagocytosis escape and evasion of host immune system responses. Targeting these proteins with monoclonal antibodies thus represents a new therapeutic option against S. aureus. To this end, here we report the selection and characterization of fully human, sequence-defined, monoclonal antibodies selected against the C-terminus of Coagulase. Given the functional homology between Coa and Efb, we also investigated if the generated antibodies bound the two virulence factors. Thirteen unique antibodies were isolated from naive antibodies gene libraries by antibody phage display. As anticipated, most of the selected antibodies showed cross-recognition of these two proteins and among them, four were able to block the interaction between Coa/Efb and Fg. Furthermore, our monoclonal antibodies could interact with the two main Fg binding repeats present at the C-terminus of Coa and distinguish them, suggesting the presence of two functionally different Fg-binding epitopes. ImportanceThe death toll related to methicillin-resistant S. aureus piled to almost 1 million people in only one year (2019), ascribing S. aureus to the second leading cause of deaths associated with antimicrobial resistance. Therefore, new therapeutic strategies must be investigated. Blocking the adhesion step with the use of monoclonal antibodies is one promising alternative and Fg is a central plasma protein involved in staphylococcal infection. We present here a panel of monoclonal antibodies raised against Coa, cross-reacting to Efb and targeting the shared Fg binding repeats of Coa. In addition, we describe new epitope determinants in the repeated region of Coa, highlighted by differential binding of the newly selected antibodies.

biochemistry↗

bioRxiv2022

KAT5 activity regulates G0-like states in human gliomas

In solid tumors, G0-like states are likely critical for maintaining developmental hierarchies and cellular heterogeneity and promoting tumor growth/recurrence, yet little is known about tumor G0 states or regulation of their ingress/egress. To discover G0-like states and their regulators for glioblastoma (GBM), we analyzed G0 populations in an orthotopic model of GBM using single cell RNA-seq and performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that trap cells in G0 when inhibited. We identify the protein acetyltransferase KAT5 as a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states. KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics both in vitro and in a human GSC brain tumor model. In primary gliomas, KAT5 activity is dynamic with KAT5low tumor cells displaying quiescent properties, while KAT5 activity overall increases from low to high grade tumors and is associated with worse patient outcomes.

cancer biology↗

bioRxiv2022

Defining cellular population dynamics at single cell resolution during prostate cancer progression

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigated prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in vivo. We observe a dramatic expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is in part androgen responsive. Androgen independent prostate cancer leads to significant diversification of intermediate luminal cell populations characterized by a range of androgen signaling activity inversely correlated with proliferation and mRNA translation. Accordingly, distinct epithelial populations are exquisitely sensitive to translation inhibition which leads to epithelial cell death, loss of pro-tumorigenic signaling, and decreased tumor heterogeneity. Our findings reveal a complex tumor environment largely dominated by castration-resistant luminal cells and immunosuppressive infiltrates.

cancer biology↗

bioRxiv2022

Molecular Dynamics Simulations Studies On The Effects Of Mutations On The Binding Affinities Between SARS-CoV-2 Spike RBD And Human ACE2

CONSPECTUSThe SARS-CoV-2 viruses had made a great impact on humankind and the world economy. Phylogenetic analysis revealed the newly identified B.1.617.1 and B.1.617.2 lineages possessed with few key mutations predominantly circulating. The signature mutations possessed by these lineages are situated in the RBD motif of S protein. Reports revealed variants L452R, T478K, and E484Q harbours in enhancement with hACE2 binding while P681R situated in furin cleavage site resulting in better transmissibility. To gain a deeper understanding of the impact of these variants (L452R, T478K and E484Q) binding with hACE2, structural dynamics at the interface between S-RBD protein and hACE2 were studied. We performed our dynamics studies with both single mutant complex (L452R, T478K and E484Q) and in the combination of triple mutants (L452R + T478K + E484Q) at 100ns in contrast with the wild type. Interfacial docking interactions and Molecular Mechanics approach exhibited that the spike mutants -L452R, T478K and E484Q harbour with higher binding affinity on hACE2 in contrast with its native spike protein. The presence of interfacial residue, intermolecular contacts such as hydrogen bonding, salt bridge and non-hydrogen bonded interactions might be the reason for its higher binding affinity. Hence the findings from our study unravelled plausible mechanism for the increase in affinities of mutants to hACE2 thus leading to higher transmissibility and infection of emerging variants. Further, the conformational alterations in the course of dynamics at the RBD motif led to enhancement of hACE2 binding and immune escape. These results suggest that the structural changes introduced by these variants enhance the binding affinities of the S protein with the hACE2 that could form the basis to further aid in designing therapeutics that could inhibit at the interface of S protein and hACE2 receptor.

bioinformatics↗

bioRxiv2022

A wheat kinase and immune receptor form the host-specificity barrier against the blast fungus

Since emerging in Brazil in 1985, wheat blast has spread throughout South America and recently appeared in Bangladesh and Zambia. We show that two wheat resistance genes, Rwt3 and Rwt4, acting as host-specificity barriers against non-Triticum blast pathotypes encode a nucleotide-binding leucine-rich repeat immune receptor and a tandem kinase, respectively. Molecular isolation of these genes allowed us to develop assays that will ensure the inclusion of these two genes in the wheat cultivars to forestall the recurrence of blast host jumps.

plant biology↗

bioRxiv2022

Oncogenic role of a developmentally regulated NTRK2 splice variant

Temporally-regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and forced over-expression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring TRK fusions. Affinity purification-mass spectrometry (AP-MS) proteomic analysis reveals TrkB.T1 has distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, TGF-{beta}, Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

cancer biology↗