Biology subjects

Yang, X.

Publications and source records attributed to Yang, X..

At least 325 records · Page 18Linked to original sources

bioRxiv2024

The Cryo-EM structure of TRPC1 and TRPC5 heterotetramer

Ion channel heteromers display distinct electrophysiological and ligand-binding properties, allowing precise modulation of cellular functions in specific tissues. Among the TRPC subtypes, the TRPC1/4/5 heteromers are the most abundant isoform in the human brain and represent a primary target for treating anxiety and depression. However, the structural organization of TRPC1/4/5 heteromers remain unclear, limiting the advancement of research on these channels. Here, we report the cryo-EM structure of TRPC1/5 heterotatramer at a resolution of 2.84 [A]. It consists of an asymmetric structure with three TRPC5 subunits and one TRPC1 subunit. Further structural and functional analysis revealed that the TRPC1 subunit contributes to an asymmetrical ion conduction pathway, a characteristic that differentiates it from TRPC5 homomers. The unique features of the TRPC1 pore loop and its interface interactions with TRPC5 were shown to play crucial roles in modulating the ion conduction properties and gating mechanisms of the heteromeric complex. In addition, we identified key residues within the gating regions that influence channel activation and ion permeability, elucidating the structural basis for the functional divergence between the TRPC1/C5 heterotetramer and TRPC5 homotetramer. Notably, TRPC5 residues were found to dominate gating mechanisms, underscoring the complex interplay between subunit composition and functional outcomes in TRPC channels. Our findings provide novel insights into the structural and functional dynamics of TRPC1/C5 heteromers, paving the way for targeted therapeutic strategies in TRPC5-related disorders.

biophysics↗

bioRxiv2024

Detecting Special Genes in Marine Symbionts: A Phylogeny-Deviation Approach Identifies Recombination-Enhancing Variants

Different microbes possess special traits that enable adaptation to their specific niches, often through specialized genes. Identifying such species-special genes provides insights into microbial physiology and offers new tools for bioengineering. However, beyond the search for orphan genes, there are few methods for detecting genes that are homologous to those in other species yet contain unusual functional regions. In investigating the extreme recombination frequency of the marine symbiont bacterium Ca. E. kahalalidifaciens, we developed a computational approach to identify vairants that substantially deviate from phylogenetic expectations. This unbiased strategy successfully identified multiple Holliday junctions-related genes in Ca. E. kahalalidifaciens as candidates responsible for its exceptional recombination capacity. Heterologous expression of these gene variants in Escherichia coli significantly enhanced recombination efficiency. These high-efficient variants offer insights into improving tools for genetic manipulations, and our gene-identification approach can be applied broadly for microbial genome mining.

bioinformatics↗

bioRxiv2024

Nitrate Promoting Hair Growth Through Enhancing Wnt/β-catenin and Downregulating TGF-β/Samd/BMP signaling pathway in C57BL/6 Mice

Nitrate found widely distributed in vegetables and fruits. It has been proved to have many physiological functions through nitrate-nitrite-NO pathway, such as attenuate oxidative stress, enhance the skeletal muscle and tone skin vascular. But the function of nitrate in regulating hair growth is unclear. Here, we evaluated potential roles of nitrate on hair growth and its mechanisms by in vivo models. Mice treated with 10mM nitrate supplementation significantly promoting hair growth, along with an increase in the number of hair follicles and thickness of dermis. We further demonstrated that Wnt3a and {beta}-catenin were highly expressed in the nitrate-treated groups, while the expression of TGF-{beta}1 was attenuated. Moreover, nitrate also increased the expression levels of growth factors (Fgf, Igf-1, and Vegf). Our data indicated that nitrate supplementation could effectively accelerate hair regrowth through activating the Wnt/{beta}-catenin and inhibiting TGF-{beta}1/Smad/BMP signaling pathway. Therefore, these findings provide support for a potential therapeutic role of nitrate in preventing and treating alopecia.

biochemistry↗

bioRxiv2024

Mapping the druggable targets displayed by human colonic enteroendocrine cells

Enteroendocrine cells (EECs) are specialized intestinal hormone-secreting cells that play critical roles in metabolic homeostasis, digestion, and gut-brain communication. They detect diverse stimuli including endocrine, immune, neuronal, microbial, and dietary signals, through a complex array of receptors, ion channels, and transporters, to modulate the release of over 20 hormones. These molecular sensors serve as potential drug targets to modulate hormone secretion, but until recently, catalogues of such targets in human colonic EECs have not been produced. To address this gap, we performed bulk and single-cell RNA sequencing on fluorescently labelled EECs isolated from human colonic organoids, identifying and cataloguing potential druggable targets. This catalogue includes receptors, orphan GPCRs, transporters, and hormones not previously reported in human colonic EECs. Comparison with murine EECs highlighted interspecies similarities and differences, key data to facilitate the design and optimise the predictive accuracy of pre-clinical models. We also functionally validated two receptors not previously identified in human EECs: IL-13R1, was expressed in both peptide-producing EECs and serotonin producing Enterochromaffin cells (ECs), and its ligand IL-13 stimulated the secretion of glucagon-like peptide-1 (GLP-1) and serotonin measured in real-time, and GPR173, which was selectively expressed in ECs and, when activated by its agonist Phoenixin-20, also promoted serotonin release. These analyses provide a valuable resource for therapeutic interventions aimed at modulating gut hormone secretion, with potential applications in treating gastrointestinal, metabolic, and other related disorders.

cell biology↗

bioRxiv2024

SenSeqNet: A Deep Learning Framework for Cellular Senescence Detection from Protein Sequences

Cellular senescence, characterized by the irreversible cessation of division in normally proliferating cells due to various stressors, presents a significant challenge in the treatment of age-related diseases. Understanding and accurately detecting cellular senescence is crucial for identifying potential therapeutic targets. However, traditional wet lab assays for detecting cellular senescence are time-consuming and labor-intensive, limiting research and drug development efficiency. There is an urgent need for computational tools allowing swift and accurate detection of cellular senescence from protein sequences. We propose SenSeqNet, a novel deep learning framework for detecting cellular senescence directly from protein sequences. The framework begins with feature extraction using the Evolutionarily Scaled Model (ESM-2), a state-of-the-art protein language model that captures evolutionary information and complex sequence patterns. The extracted embeddings are then passed through a hybrid architecture consisting of long short-term memory (LSTM) networks and convolutional neural networks (CNNs) to further refine and learn from the embedded information. SenSeqNet achieved a final accuracy of 83.55% on independent testing, surpassing various machine learning and deep learning architectures. This performance underscoring the robustness and effectiveness of SenSeqNet for detecting cellular senescence from protein sequences. These results provide a solid foundation for future research on aging and age-related therapeutics.

bioinformatics↗

bioRxiv2024

Mechanistic insights into structure-based design of a Lyme disease subunit vaccine

The quality of protective immunity plays a critical role in modulating vaccine efficacy, with native antigens often not able to trigger sufficiently strong immune responses for pathogen killing. This warrants creation of structure-based vaccine design, leveraging high-resolution antigen structures for mutagenesis to improve protein stability and efficient immunization strategies. Here, we investigated the mechanisms underlying structure-based vaccine design using CspZ-YA, a vaccine antigen from Borrelia burgdorferi, the bacteria causing Lyme disease (LD), the most common vector-borne disease in the Northern Hemisphere. Compared to wild-type CspZ-YA, we found CspZ-YAI183Y and CspZ-YAC187S required lower immunization frequency to protect mice from LD-associated manifestations and bacterial colonization. We observed indistinguishable human and mouse antigenicity between wild-type and mutant CspZ-YA proteins after native infection or active immunization. This supports our newly generated, high-resolution structures of CspZ-YAI183Y and CspZ-YAC187S, showing no altered surface epitopes after mutagenesis. However, CspZ-YAI183Y and CspZ-YAC187S favored the interactions between helices H and I, consistent with their elevated thermostability. Such findings are further strengthened by increasing ability of protective CspZ-YA monoclonal antibodies in binding to CspZ-YA at a physiological temperature (37{degrees}C). Overall, this study demonstrated enhanced intramolecular interactions improved long-term stability of antigens while maintaining protective epitopes, providing a mechanism for structure-based vaccine design. These findings can ultimately be extended to other vaccine antigens against newly emerging pathogens for the improvement of protective immunity.

immunology↗

bioRxiv2024

Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity

To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRASG12D mutant alleles. We defined the spectrum of oncogenic potential for nearly all possible KRAS variants, identifying several novel transforming alleles and elucidating a model to describe the frequency of KRAS mutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRASG12D second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.

cancer biology↗

bioRxiv2024

Using synthetic RNA to benchmark poly(A) length inference from direct RNA sequencing.

Polyadenylation is a dynamic process which is important in cellular physiology. Oxford Nanopore Technologies direct RNA-sequencing provides a strategy for sequencing the full-length RNA molecule and analysis of the transcriptome and epi-transcriptome. There are currently several tools available for poly(A) tail-length estimation, including well-established tools such as tailfindr and nanopolish, as well as two more recent deep learning models: Dorado and BoostNano. However, there has been limited benchmarking of the accuracy of these tools against gold-standard datasets. In this paper we evaluate four poly(A) estimation tools using synthetic RNA standards (Sequins), which have known poly(A) tail-lengths and provide a valuable approach to measuring the accuracy of poly(A) tail-length estimation. All four tools generate mean tail-length estimates which lie within 12% of the correct value. Overall, Dorado is recommended as the preferred approach due to its relatively fast run times, low coefficient of variation and ease of use with integration with base-calling.

bioinformatics↗

bioRxiv2024

Does Unfairness Evoke Anger or Disgust? A Quantitative Neurofunctional Dissection Based on 25 Years of Neuroimaging

Over the last decades, the traditional Homo economicus model has been increasingly challenged by convergent evidence underscoring the impact of emotions on decision-making. A classic example is the perception of unfairness operationalized in the Ultimatum Game where humans readily sacrifice personal gains to punish those who violate fairness norms. While the emotional mechanism underlying costly punishments has been widely acknowledged, the distinct contributions of moral emotions (anger or disgust) remain debated, partly due to methodological limitations of the conventional experiments. Here, we capitalize on a quantitative neurofunctional dissection approach by combining recent developments in neuroimaging meta-analyses, behavioral-level, network-level, and neurochemical-level decoding and data from 3,266 participants from functional neuroimaging studies to determine the common and distinct neural representations between unfairness and the two moral emotions. Experience of unfairness engaged a widespread bilateral network encompassing insular, cingulate, and frontal regions, with dorsal striatal regions mediating the decision to reject unfair offers. Disgust engaged a defensive-avoidance circuit encompassing amygdalar, occipital, and frontal regions, while anger engaged non-overlapping systems including mid-cingulate, thalamic, and frontal regions. Unfairness and anger or disgust respectively commonly engaged the anterior and mid-insula, while the latter additionally showed common recruitment of ventrolateral prefrontal and orbitofrontal cortices. Multimodal network, behavioral, and serotonergic decoding provided a more granular and convincing dissection of these results. Findings indicate a shared neuroaffective basis underlying the impact of emotions on unfairness-induced punishment behavior and suggest a common brain circuit has been evolutionarily shaped to protect individuals from personal harm and enforce societal norms.

neuroscience↗

bioRxiv2024

In vivo CRISPRi screen identified lncRNA portfolio crucial for cutaneous squamous cell carcinoma tumor growth

Cutaneous squamous cell carcinoma (cSCC) accounts for 20% of all skin cancer deaths globally, making it the second-highest subtype of skin cancer. The prevalence of cSCC in humans, as well as the poor capacity for an efficient prognosis, highlights the need to uncover alternative actors and mechanisms at the foundation of skin cancer development. Significant advances have been made to better understand some key factors in cSCC progression. However, little is known about the role of noncoding RNAs, particularly of a specific category called long noncoding RNA (lncRNA). By performing pseudobulk analysis of single-cell sequencing data from normal and cSCC human skin tissues, we determined a global portfolio of lncRNAs specifically expressed in keratinocyte subpopulations. Integration of CRISPR interference screens in vitro and the xenograft model identified several lncRNAs impacting the growth of cSCC cancer lines both in vitro and in vivo. Among these, we further validated LINC00704 and LINC01116 as proliferation-regulating lncRNAs in cSCC lines and potential biomarkers of cSCC progression. Taken together, our study provides a comprehensive signature of lncRNAs with roles in regulating cSCC progression.

cancer biology↗

bioRxiv2024

Myosin light chain 3 serves as a receptor for nervous necrosis virus entry into host cells via the macropinocytosis pathway

Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (Oryzias melastigma) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which dependents on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3s crucial role in NNV entry and its potential as an antiviral target.

microbiology↗

bioRxiv2024

Assembloid model to study loop circuits of the human nervous system

Neural circuits connecting the cerebral cortex, the basal ganglia and the thalamus are fundamental networks for sensorimotor processing and their dysfunction has been consistently implicated in neuropsychiatric disorders1-9. These recursive, loop circuits have been investigated in animal models and by clinical neuroimaging, however, direct functional access to developing human neurons forming these networks has been limited. Here, we use human pluripotent stem cells to reconstruct an in vitro cortico-striatal-thalamic-cortical circuit by creating a four-part loop assembloid. More specifically, we generate regionalized neural organoids that resemble the key elements of the cortico-striatal-thalamic-cortical circuit, and functionally integrate them into loop assembloids using custom 3D-printed biocompatible wells. Volumetric and mesoscale calcium imaging, as well as extracellular recordings from individual parts of these assembloids reveal the emergence of synchronized patterns of neuronal activity. In addition, a multi-step rabies retrograde tracing approach demonstrate the formation of neuronal connectivity across the network in loop assembloids. Lastly, we apply this system to study heterozygous loss of ASH1L gene associated with autism spectrum disorder and Tourette syndrome and discover aberrant synchronized activity in disease model assembloids. Taken together, this human multi-cellular platform will facilitate functional investigations of the cortico-striatal-thalamic-cortical circuit in the context of early human development and in disease conditions.

neuroscience↗

bioRxiv2024

Bacterial sensing via Neuronal Receptor Initiates Gut Mitochondrial Surveillance for Host Adaptation

Animals exist within a microbial world and are constantly challenged by pathogen infections. Microbe-mediated protection for against infection is the survival strategy for host. However, elucidating specific microbial molecules and understanding how they interact with the hosts intracellular surveillance system for protection is difficult but highly desirable. Here, by establishing "pathogen-like-bacteria" screening system, we identified E. coli mutants, including {Delta}ymcB, that act as "pathogen-like-bacteria" to defend animals against Pseudomonas aeruginosa PA14 infection by activating UPRmt. Additionally, through genetic screening, we identified neuronal transmembrane protein, MDSS-1, that is crucial for sensing {Delta}ymcB and activating intestinal UPRmt. Moreover, we demonstrated that MDSS-1 functions as a receptor in ASE neurons, responsible for detecting {Delta}ymcB. It then communicates microbial signals through neuropeptides, GPCR, Wnt signaling and endopeptidase inhibitors to trigger intestinal UPRmt, that defends the host animals against infections. Furthermore, Constitutionally activation of MDSS-1 in ASE neurons is sufficient to trigger intestinal UPRmt in animals, resulting in protection against infection. Our study uncovers an intriguing mechanism involving intracellular mitochondrial surveillance, where neuron-intestine crosstalk originates from ASE neurons to detect bacteria and combat pathogens. This study identifies a bacteria-sensing mechanism in neurons that regulates intestinal mitochondrial surveillance pathway for host adaptation. HighlightsO_LIEstablishment of "pathogen-like-bacteria" screening system in C. elegans C_LIO_LI{Delta}ymcB promotes animal defend against infections via triggering UPRmt C_LIO_LINeuronal MDSS-1, a single transmembrane protein, detects "pathogen-like-bacteria" C_LIO_LIActivated-MDSS-1 induces distant UPRmt via inter-tissue communication factors C_LI

physiology↗

bioRxiv2024

A brassinosteroid receptor kinase is required for sex determination in the homosporous fern Ceratopteris richardii

Most ferns, unlike all seed plants, are homosporous and produce sexually undifferentiated spores. Sex in many homosporous ferns is environmentally regulated by the biosynthesis of antheridiogens. Secreted antheridiogen from female or hermaphrodite gametophytes is perceived by undetermined gametophytes which respond by developing as male. In the fern Ceratopteris richardii (Ceratopteris), several hermaphroditic (her) mutants develop as hermaphrodites even in the presence of antheridiogen. A set of five mutant alleles are tightly linked to her7, a locus of unknown molecular identity. The immense size of the Ceratopteris genome has made efficient identification of the underlying genes a challenge. Here, we used bulked segregant RNA-seq (BSR-Seq) to map two her mutants (her7-14 and her7-19) to a 16 Mbp interval on chromosome 29 of the Ceratopteris genome. A brassinosteroid receptor-like kinase (BRL) within this interval encoded a deletion mutation in her7-14 and a missense mutation in her7-19. Three other linked her mutants (her7-1, her7-11, and her7-15) encoded missense mutations in the same gene, which we name HER7, providing strong support for HER7 being required for antheridiogen-mediated sex determination in Ceratopteris. HER7-GFP fusion protein is localized in the plasma membrane and cytoplasm, consistent with its predicted function as a brassinosteroid receptor kinase. RNA-seq analysis of gene expression shows that numerous transcripts encoding enzymes, including those for brassinosteroid biosynthesis, accumulate in hermaphrodites compared to male gametophytes. The antheridiogen of Ceratopteris is currently unknown and our finding that a BRL mutant is insensitive to antheridiogen suggests that antheridiogen in Ceratopteris may be a brassinosteroid. Additional work is required to fully resolve the sex determination pathway and determine the chemical composition of antheridiogen in this species. Our work demonstrates we can identify the molecular basis of mutants in large genomes, such as those in homosporous ferns, which can be further applied to the extensive remaining collection of mutants in Ceratopteris.

genetics↗

bioRxiv2024

A host-directed adjuvant resuscitates and sensitizes intracellular bacterial persisters to antibiotics

There are two major problems in the field of antimicrobial chemotherapy-antibiotic resistance and antibiotic tolerance. In the case of antibiotic tolerance, antibiotics fail to kill the bacteria as their phenotypic state affords them protection from the bactericidal activity of the antibiotic. Antibiotic tolerance can affect an entire bacterial population, or a subset of cells known as persister cells. Interaction with the host induces the formation of persister cells in numerous pathogens, with reactive oxygen and nitrogen species production being heavily implicated in the collapse of bacterial energy levels and entrance into an antibiotic tolerant state. Here, we developed a high-throughput screen to identify energy modulators for intracellular Staphylococcus aureus. The identified compound, KL1, increases intracellular bacterial energy and sensitizes the persister population to antibiotics, without causing cytotoxicity or bacterial outgrowth. We demonstrate that KL1 exhibits adjuvant activity in a murine model of S. aureus bacteremia and intracellular infection of Salmonella Typhimurium. Transcriptomic analysis and further studies on its mechanism of action reveal that KL1 modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating one of the major stressors that induce antibiotic tolerance. Our findings highlight the potential to target intracellular persister cells by stimulating their metabolism and encourage larger efforts to address antibiotic tolerance at the host-pathogen interface, particularly within the intracellular milieu.

microbiology↗

bioRxiv2024

Ribozyme-based biosensor for imaging gene expression in plants

Detection of gene expression in plants is critical for understanding the molecular basis of complex plant biosystems and plant responses to environmental stresses. Here, we report the development of a split ribozyme-based biosensor that enables in vivo visualization of gene expression in plants. We demonstrated the utility of this biosensor in transient expression experiments (i.e., leaf infiltration in Nicotiana benthamiana) to detect RNAs derived from transgenes and tobacco rattle virus, respectively. Furthermore, we successfully engineered a split ribozyme-based biosensor in Arabidopsis thaliana for in vivo visualization of endogenous gene expression at the cellular level. In addition, we developed a platform for easy incorporation of different reporters into the RNA biosensor.

synthetic biology↗

bioRxiv2024

Pexidartinib plus FLT3-directed CAR-Macrophage for the treatment of FLT3-ITD-mutated acute myeloid leukemia in preclinical model

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations occur in about 25%-30% of AML cases and are associated with adverse prognosis. Recent advances indicate that M2-like leukemia-associated macrophages (M2-LAM) are highly infiltrated in the bone marrow of FLT3-ITD+ AML patients; however, the underlying mechanisms and therapeutic implications are still elusive. Herein, we reveal that conditioned medium from FLT3-ITD+ MOLM-13 AML cells polarized M2-LAM and impaired their phagocytic activities. Unexpectedly, co-culture of M2-LAM protected MOLM-13 cells from the treatment of FLT3 inhibitor quizartinib by activating their FLT3 signaling pathway. Pharmaceutically, FLT3/CSF1R dual inhibitor pexidartinb effectively suppressed M2-LAM, reduced leukemic burden, and prolonged the survival of MOLM-13-xenografted mice. To enhance the phagocytic activities of macrophages, FLT3-directed chimeric antigen receptor-engineered macrophages (FLT3L-CAR-Macrophage) were generated using FLT3 ligand (FLT3L) as the recognizing domain of CAR. Transfection of THP-1 monocytic cells-or umbilical cord blood mononuclear cells-derived macrophages with FLT3L-CAR-encoding mRNA enhanced their phagocytic activities to MOLM-13 cells in vitro. Consistently, FLT3L-CAR-Macrophage differentiated from FLT3L-CAR-expressing THP-1 cells effectively phagocytosed MOLM-13 cells in vitro, reduced leukemic burden and prolonged the survival of MOLM-13-xenografted mice. Importantly, treatment of pexidartinib resulted in upregulation and surface localization of FLT3-ITD protein in MOLM-13 cells, sensitized MOLM-13 cells to the treatment of FLT3L-CAR-Macrophage in vitro, and synergized with FLT3L-CAR-Macrophage to further reduce leukemic burden in MOLM-13-xenografted mice. Together, our data indicate that pexidartinib plus FLT3L-CAR-Macrophage could be a promising therapeutic strategy for the treatment of FLT3-ITD+ AML in preclinical model which warrants further investigation. Graphical AbstractPexidartinib plus FLT3L-CAR-M{varphi} for the treatment of FLT3-ITD+ AML in preclinical model. Pexidartinib suppressed AML growth, reduced M2-LAM, increased FLT3 surface expression and synergized with FLT3L-CAR-M{varphi} to target FLT3-ITD+ AML in vitro and in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/615313v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1e7c0f4org.highwire.dtl.DTLVardef@2cdf6eorg.highwire.dtl.DTLVardef@e84borg.highwire.dtl.DTLVardef@1929d28_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Regulation of tmTNF-α Processing by FRMD8 in Triple-Negative Breast Cancer Metastasis: Insights into Molecular Pathway Dynamics

PurposeBreast cancer remains the leading cause of cancer-related mortality among women worldwide, with late-stage diagnoses prevalent in China resulting in significantly lower survival rates. This study focuses on identifying genes implicated in breast cancer metastasis, highlighting the role of Tumor Necrosis Factor-alpha (TNF-) and its forms--transmembrane (tmTNF-) and soluble (sTNF-). Experimental DesignTNF- is crucial for activating NF-{kappa}B pathways that regulate genes involved in cell adhesion, migration, and immune evasion, all essential for cancer metastasis. We conducted comprehensive analyses of FRMD8, a member of the FERM domain-containing proteins, as a significant regulator of tmTNF-. Through integrative multi-omics and cellular functional studies, the relationship between FRMD8, iRhom2, and ADAM17 was assessed in the context of breast cancer metastasis. ResultsOur findings reveal that FRMD8 forms a complex with iRhom2 and ADAM17, enhancing the stability and sheddase activity of ADAM17, which is vital for the release of TNF-. The absence of FRMD8 leads to decreased ADAM17 activity, increasing the availability of tmTNF- and potentially promoting metastasis. This effect suggests that FRMD8 is a key modulator of TNF- processing. ConclusionsThis study explores how FRMD8 influences TNF- processing and the metastatic behavior of breast cancer, providing insights into molecular dynamics that could guide future therapeutic strategies to improve outcomes in breast cancer patients.

cancer biology↗