Biology subjects

Flaherty, K.

Publications and source records attributed to Flaherty, K..

10 recordsLinked to original sources

bioRxiv2024

Evolutionary conserved reciprocal senescence and tumor suppressor signals limit lifetime cancer

Cellular senescence features a durable exit from the cell cycle triggered by stress or carcinogens. The INK4 locus is inactivated in various cancers, yet in senescence, p16Ink4a is activated. Whether senescence is tumor-suppressing or -promoting remains a conundrum. We discovered an evolutionally-conserved Vertebrata INK4-homolog. This ink4ab triggers senescence upon oxidative- and/or carcinogenic-stress. Adult Ink4ab-deficient animals failed to activate senescence and developed spontaneous cancers. Combined Ink4ab and Tp53 deficiency revealed a reciprocal senescence and apoptosis regulation, controlling tumorigenesis, including retinoblastoma. INK4-hematopoietic-deficient mice exhibited p19Arf-dependent enhanced senescence-like phenotypes, uncontrolled cell proliferation, defective stem cell differentiation, and splenomegaly, with single-splenocytes spatially-enriched in senescence-associated secretory profiles. Our studies reveal the evolutionary origin of paradigms co-regulating senescence and tumor suppression and offer strategies to exploit these reciprocal pathways for cancer prevention and therapy.

cancer biology↗

bioRxiv2024

DeepVul: A Multi-Task Transformer Model for Joint Prediction of Gene Essentiality and Drug Response

Despite their potential, current precision oncology approaches benefit only a small fraction of patients due to their limited focus on actionable genomic alterations. To expand its applicability, we propose DeepVul, a multi-task transformer-based model designed to predict gene essentiality and drug response from cancer transcriptome data. DeepVul aligns gene expressions, gene perturbations, and drug perturbations into a latent space, enabling simultaneous and accurate prediction of cancer cell vulnerabilities to numerous genes and drugs. Benchmarking against existing precision oncology approaches revealed that Deep-Vul not only matches but also complements oncogene-defined precision methods. Through interpretability analyses, DeepVul identifies underlying mechanisms of treatment response and resistance, as demonstrated with BRAF vulnerability prediction. By leveraging whole-genome transcriptome data, DeepVul enhances the clinical actionability of precision oncology, aiding in the identification of optimal treatments across a broader range of cancer patients. DeepVul is publicly available at https://github.com/alaaj27/DeepVul.git.

bioinformatics↗

bioRxiv2024

A balanced CAR-T cell metabolism driven by CD28 or 4-1BB co-stimulation correlates with clinical success in lymphoma patients

Chimeric antigen receptor (CAR) T cell therapy has led to unprecedented success in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL). The most common CAR-T cell products currently in the clinic for DLBCL differ in their co-stimulation moiety, containing either CD28 or 4-1BB, which initiate distinct signalling pathways. Previous work has highlighted the importance of T cell metabolism in fuelling anti-cancer function. We have studied the metabolic characteristics induced by CD28 versus 4-1BB co-stimulation in patient CAR-T cells ex vivo. Our data show that in patients, CD28 and 4-1BB drive significantly divergent metabolic profiles. CD28 signalling endows T cells with a preferentially glycolytic metabolism supporting an effector phenotype and increased expansion capacity, while 4-1BB co-stimulation preserves mitochondrial fitness and results in memory-like differentiation. Despite this divergent programming, T cells in patients responding successfully to therapy were metabolically similar, irrespective of co-stimulator, suggesting that efficient fuelling of CAR-T cells in lymphoma requires a balanced metabolism. In contrast, CAR-T cells in non-responders were pushed to their metabolic extremes. One sentence summaryCD28 and 4-1BB signalling drive divergent metabolic profiles in patient CAR-T cells, however patients that respond to therapy have CAR-T cells that maintain metabolic balance.

immunology↗

bioRxiv2024

A Comprehensive Proteogenomic and Spatial Analysis of Innate and Acquired Resistance of Metastatic Melanoma to Immune Checkpoint Blockade Therapies

While a subset of patients with metastatic melanoma achieves durable responses to immune checkpoint blockade (ICB) therapies, the majority ultimately exhibit either innate or acquired resistance to these treatments. However, the molecular mechanisms underlying resistance to ICB therapies remain elusive and are warranted to elucidate. Here, we comprehensively investigated the tumor and tumor immune microenvironment (TIME) of paired pre- and post-treatment tumor specimens from metastatic melanoma patients who were primary or secondary resistance to anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies. Differentially expressed gene (DEG) analysis and single-sample gene set enrichment analysis (ssGSEA) with transcriptomic data identified cell cycle and c-MYC signaling as pathway-based resistance signatures. And weighted gene co-expression network analysis (WGCNA) revealed the activation of a cross-resistance meta-program involving key signaling pathways related to tumor progression in ICB resistant melanoma. Moreover, spatially-resolved, image-based immune monitoring analysis by using NanoStrings digital spatial profiling (DSP) and Cyclic Immunofluorescence (CyCIF) showed infiltration of suppressive immune cells in the tumor microenvironment of melanoma with resistance to ICB therapies. Our study reveals the molecular mechanisms underlying resistance to ICB therapies in patients with metastatic melanoma by conducting such integrated analyses of multi-dimensional data, and provides rationale for salvage therapies that will potentially overcome resistance to ICB therapies. Statement of translational relevanceThis study paves the way for the creation of innovative therapeutic strategies, aimed at subverting resistance to immune checkpoint blockade (ICB) therapies in metastatic melanoma patients. By unraveling the specific molecular mechanisms underlying resistance, scientists can design effective alternative treatments that target pathways such as pathways associated with cell cycle dysregulation and c-MYC signaling. Furthermore, through the application of advanced immune monitoring techniques such as NanoString Digital Spatial Profiling (DSP) and Cyclic Immunofluorescence (CyCIF), this study has significantly enriched our understanding of the tumor microenvironment. This enhanced characterization facilitates the discovery of potential biomarkers that may forecast a patients response to ICB treatment. Ultimately, these advancements could potentially refine patient outcomes and foster the development of more personalized cancer treatments in the future.

genetics↗

bioRxiv2023

Distinct ossification trade-offs illuminate the shoulder girdle reconfiguration at the water-to-land transition.

The mechanisms of the pectoral girdle transformation at the origin of terrestrial locomotion in vertebrates remains an outstanding problem in evolutionary biology1. The loss of dermal bones and the enlargement of endochondral bones resulted in the disarticulation of the pectoral girdle from the skull and the formation of the neck during the fish-to-tetrapod transition2-5. Despite the functional implications of this skeletal shift in the emergence of terrestrial vertebrates, the underlying genetic-developmental alterations have remained enigmatic. Here, we discovered that in zebrafish pectoral girdle mesodermal cells expressing gli3, a transcription factor in the Hedgehog signaling pathway, contribute to both dermal and endochondral bones. We show that Gli3 regulates expression of activin A receptor type 1-like, a BMP type 1 receptor lost in tetrapod lineages, and thereby determines endochondral and dermal ossification. Intriguingly, Gli and Hedgehog compound knockout fish exhibited an unexpected combination of actinopterygian fish and stem-tetrapod pectoral girdle characteristics. These ontogenetic and anatomical data suggest that a trade-off between the two distinct ossification pathways is a deeply embedded developmental program in bony fishes, with potential for tuning of this trade-off to generate novel pectoral girdle forms akin to stem-tetrapods at the dawn of vertebrate terrestrialization.

evolutionary biology↗

bioRxiv2022

Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma

The RAS-RAF-MEK-ERK pathway is hyperactivated in almost all malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors are highly efficient for treating patients with BRAFV600E mutations, but tumours frequently acquire resistance within a few months. Multiple resistance mechanisms have been identified, due to mutations or network adaptations that revive ERK signalling. We have previously shown that RAF proteins inhibit the MST2 proapoptotic pathway in a kinase independent fashion. Here, we have investigated the role of the MST2 pathway in mediating resistance to BRAF inhibitors. We show that the BRAFV600E mutant protein, but not the wildtype BRAF protein, strongly binds to MST2 and inhibits MST2 pro-apoptotic signalling. Downregulation of MST2 reduces BRAF inhibitor induced apoptosis. In BRAF inhibitor resistant cell lines MST2 pathway proteins are downregulated by ubiquitination and subsequent proteasomal degradation rendering cells refractory to MST2 pathway induced apoptosis. Restoration of apoptosis can be achieved by increasing MST2 pathway protein expression using proteasome inhibitors. In summary, we show that the MST2 pathway plays a role in the acquisition of BRAF inhibitor resistance in melanoma.

molecular biology↗

bioRxiv2021

Intermittent brain network reconfigurations and the resistance to social media influence

Since their development, social media has grown as a source of information and has a significant impact on opinion formation. Individuals interact with others and content via social media platforms in a variety of ways but it remains unclear how decision making and associated neural processes are impacted by the online sharing of informational content, from factual to fabricated. Here, we use EEG to estimate dynamic reconfigurations of brain networks and probe the neural changes underlying opinion change (or formation) within individuals interacting with a simulated social media platform. Our findings indicate that the individuals who changed their opinions are characterized by less frequent network reconfigurations while those who did not change their opinions tend to have more flexible brain networks with frequent reconfigurations. The nature of these frequent network configurations suggests a fundamentally different thought process between intervals in which individuals are easily influenced by social media and those in which they are not. We also show that these reconfigurations are distinct to the brain dynamics during an in-person discussion with strangers on the same content. Together, these findings suggest that brain network reconfigurations may not only be diagnostic to the informational context but also the underlying opinion formation. Author SummaryDistinctive neural underpinnings of opinion formation and change during in-person and online social interactions are not well understood. Here, we analyze EEG recordings of the participants interacting with a simulated social media platform and during an in-person discussion using a network-based analysis approach. We show that the structure of network reconfigurations during these interactions is diagnostic of the opinion change and the context in which information was received.

neuroscience↗

bioRxiv2021

Data-driven discovery of targets for bipotent anticancer drugs identifies Estrogen Related Receptor Alpha

Drugs that kill tumors through multiple mechanisms have potential for broad clinical benefits, with a reduced propensity to resistance. We developed BipotentR, a computational approach to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway. Using tumor metabolism as proof-of-principle, BipotentR identified 38 candidate immune-metabolic regulators by combining epigenomes with bulk and single-cell tumor transcriptomes from patients. Inhibition of top candidate ESRRA (Estrogen Related Receptor Alpha) killed tumors by direct effects on energy metabolism and two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8+T cells into tumors. ESRRA is activated in immune-suppressive and immunotherapy-resistant tumors of many types, suggesting broad clinical relevance. We also applied BipotentR to angiogenesis and growth-suppressor pathways, demonstrating a widely applicable approach to identify drug targets that act simultaneously through multiple mechanisms. BipotentR is publicly available at http://bipotentr.dfci.harvard.edu/. One-Sentence SummaryBipotentR identifies targets for bipotent anticancer drugs, as shown by the energy and immune effects of ESRRA inhibition.

cancer biology↗

bioRxiv2019

The evolutionary origins and diversity of the neuromuscular system of paired appendages in batoids

Appendage patterning and evolution have been active areas of inquiry for the past two centuries. While most work has centered on the skeleton, particularly that of amniotes, the evolutionary origins and molecular underpinnings of the neuromuscular diversity of fish appendages have remained enigmatic. The fundamental pattern of segmentation in amniotes, for example, is that all muscle precursors and spinal nerves enter either the paired appendages or body wall at the same spinal level. The condition in finned vertebrates is not understood. To address this gap in knowledge, we investigated the development of muscles and nerves in unpaired and paired fins of skates and compared them to those of chain catsharks. During skate and shark embryogenesis, cell populations of muscle precursors and associated spinal nerves at the same axial level contribute to both appendages and body wall, perhaps representing an ancestral condition of gnathostome appendicular neuromuscular systems. Remarkably in skates, this neuromuscular bifurcation as well as colinear Hox expression extend posteriorly to pattern a broad paired fin domain. In addition, we identified migratory muscle precursors (MMPs), which are known to develop into paired appendage muscles with Pax3 and Lbx1 gene expression, in the dorsal fins of skates. Our results suggest that muscles of paired fins have evolved via redeployment of the genetic program of MMPs that were already involved in dorsal fin development. Appendicular neuromuscular systems most likely have emerged as side branches of body wall neuromusculature and have been modified to adapt to distinct aquatic and terrestrial habitats.

evolutionary biology↗

bioRxiv2018

Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here we perform a genome-wide prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.

cancer biology↗