Biology subjects

Phillip, J. M.

Publications and source records attributed to Phillip, J. M..

At least 19 recordsLinked to original sources

bioRxiv2026

Intravital single-cell behavior profiling reveals disrupted germinal center B cell motility and interactions by EZH2 gain-of-function mutation

Germinal center (GC) B-cells give rise to the majority of non-Hodgkin lymphomas, underscoring the need to pinpoint critical processes that initiate and drive lymphomagenesis. Lymphoma driver mutations can alter GC B cell functions and B cell fate decisions. Here, we studied how EZH2 oncogenic mutation in GC B cells alters cellular motility and interactions with T follicular helper (Tfh) cells and follicular dendritic cells (FDCs) to determine B cell fate. By combining intravital imaging, single-cell behavior analyses, and RNA sequencing, we uncover how lymphoma-associated EZH2 mutations reprogram the behaviors of GC B cells in vivo. We found that EZH2 mutations increased single-cell motility speeds and morphological plasticity of GC B cells, redirecting migration toward the FDC-rich light zone subregions rather than to the dark zone. Although mutant EZH2 GC B cells exhibited normal engagement quality with FDCs, they showed shorter interaction times and reduced surface engagement with Tfh cells. Notably, EZH2 mutant B cells required prior contact with FDC before engaging with Tfh cells, thus impairing DZ recycling. This motility phenotype scaled with local mutant clone abundance, suggesting a behavioral strategy underlying how mutant cells outcompete WT cells. Lastly, we developed scMOTIPh, a computational framework that integrates single-cell behavioral features with transcriptomic profiles. Applying scMOTIPh to mutant GC B cells within the FDC-rich zone revealed enhanced ATP production, metabolic and antigen-presentation programs, and suppression of cell-death pathways, which is consistent with a tendency for malignant transformation and survival fitness. These findings provide an in vivo, single-cell view of how an epigenetic lesion rewires the local microenvironment by modulating single-cell behaviors within native GCs, revealing a dynamic mechanism for early lymphomagenesis.

immunology↗

bioRxiv2026

Senescent cell networks link matrix remodeling and vascular dysfunction in human fibroids

Uterine fibroids (leiomyomas) are highly prevalent benign tumors defined by excessive extracellular matrix (ECM) deposition, altered vascular structure, and progressive tissue stiffening, yet the cellular programs that coordinate these features remain poorly understood. Cellular senescence has been implicated in fibroid biology, but whether senescence represents a uniform state or distinct, functionally specialized cell identities within fibroids is unknown. Here, we identify the distinct heterogeneous populations of senescent cells ("senotypes") present in human fibroids and characterize their role in shaping the fibroid microenvironment. Using single-cell RNA sequencing (scRNA-seq) integrated with a senescence gene signature and protein-level validation, we identify senescent cells (SnC) distributed across fibroblast, mural, and endothelial compartments, each exhibiting distinct transcriptional programs. SnC endothelial cells (ECs) are enriched in fibroids relative to matched myometrium and activate TEAD4-associated mechanosensing, angiogenic, and immune signaling pathways, despite being associated with impaired vessel maturation in situ. In parallel, SnC fibroblast and mural populations in fibroids upregulated SRF-associated cytoskeletal and ECM programs, accompanied by increased COL6A3 expression and collagen VI deposition, consistent with tissue stiffening. Ligand-receptor and spatial analyses reveal that these SnC populations function as interconnected signaling hubs, coordinating immune cell recruitment and stromal remodeling. Importantly, analysis of human fibroids treated with collagenase demonstrated a reduction in both ECM density and SnC burden, supporting a reinforcing relationship between matrix mechanics and senescence. Together, these findings establish senescence in fibroids as a heterogeneous, mechanically reinforced, and network-driven process that links vascular dysfunction, immune signaling, and fibrosis, highlighting distinct SnC states as potential translational targets for non-surgical therapies.

cell biology↗

bioRxiv2026

Behavioral and Functional Profiling of Acomys cahirinus Fibroblasts Reveals Enhanced Matrix Remodeling Capacity

The African spiny mouse (Acomys cahirinus) exhibits a unique capacity among mammals for scarless tissue regeneration, making it a compelling model for investigating the cellular mechanisms underlying regenerative healing. To determine how cellular heterogeneity and specific phenotypes influence fibroblast behavior, we established an immortalized Acomys fibroblast line along with a CRISPR/Cas9-mediated Col3A1 knockout variant and a DNA damage-induced senescent population. Compared with Mus musculus, NIH 3T3 fibroblasts, Acomys cells displayed distinct morphology, similar migration speeds, reduced directional persistence, and greater biophysical heterogeneity. While previous studies have linked regenerative wound healing to the elevated expression of collagen type III (Col3A1), CRISPR-mediated knockout of Col3A1 in Acomys fibroblasts yielded comparable biophysical profiles to wild-type cells in 2D culture. To examine additional contributors to the enhanced wound-like matrix environment, we established a senescence model in which Acomys fibroblasts exhibited elevated resistance to DNA-damaging agents, complete loss of proliferation, and altered single-cell morphology. In 3D collagen gel contraction assays, Col3A1 knockout attenuated matrix remodeling capacity, whereas the introduction of a small fraction of senescent cells enhanced gel contraction and remodeling dynamics, suggesting that senescent fibroblasts can modulate collective matrix behaviors. Together, these findings demonstrate that both Col3A1 expression and senescence-associated cell states contribute to fibroblast-driven matrix remodeling, highlighting Acomys fibroblasts as a valuable model for investigating how cellular heterogeneity and senescence-associated cell phenotypes could influence regenerative wound healing.

bioengineering↗

bioRxiv2026

Neutrophil migration in the lung is altered by alveolar collapse and stretch

RationaleHeterogeneous alveolar collapse is prevalent in inflammatory lung conditions such as chronic obstructive pulmonary disease, acute respiratory distress syndrome, and pneumonia. Although neutrophil-released proteases contribute to the tissue remodeling that leads to alveolar collapse, how this altered mechanical environment in turn affects neutrophil migration remains largely unexplored. ObjectivesIn this study, we investigate how alveolar collapse and stretch influence neutrophil migration and identify the mechanical and biochemical factors that govern regional migration differences. MethodsWe developed a novel precision-cut lung slice platform that generates collapsed vs non-collapsed regions within the same slice. Neutrophils in both regions were longitudinally imaged for up to 5 hours to quantify motility behavior. Migration mechanisms were probed using migration-related inhibitors, collagenase, and cigarette smoke extract. A crystal ribcage system, which preserves intact alveolar shape and the air-liquid interface, was also used to assess the effects of ventilation on neutrophil migration. ResultsNeutrophil migration was faster in the collapsed region compared to not-collapsed regions. This regional difference was eliminated by Rho-associated protein kinase (ROCK) inhibition, which selectively increased migration speed in the non-collapsed region. The regional difference persisted with the addition of collagenase and cigarette smoke extract, both of which significantly increased the migration speed in both regions. In the crystal ribcage, the preserved air-liquid interface and ventilation together enhanced neutrophil migration compared with a collapsed lung. ConclusionsAlveolar collapse and stretch facilitate neutrophil migration, indicating the role of localized tissue remodeling in driving neutrophil activity and further disease progression.

bioengineering↗

bioRxiv2026

Cell-nanoplastics association impacts cell proliferationand motility

Detection of micro- and nanoplastics (MNPs) in human tissues has raised growing concern about their biological effects on tissue and cell function. While previous studies have examined MNP-cell interaction, most focused on limited cell and plastic types. Here, we present a comprehensive, quantitative investigation into how different types of nanoplastics (NPs) associate with and affect diverse cell types under physiologically relevant conditions. Using microfluidic-calibrated fluorescence microscopy, we quantify NP accumulation in cells in vitro and match cellular NP concentrations to levels reported in human tissues. While cell-associated NPs could be gradually released in vitro, they persist in vivo for over one month without detectable reduction in a mouse model. We discover that NP exposure at these levels broadly impairs cell proliferation across epithelial, endothelial, fibroblast, and immune cells, with cell type-dependent sensitivity. NP exposure also reduces motility in T cells and fibroblasts, with more complex effects observed in macrophages. Mechanistically, NP-cell association and trans-epithelial transport involved not only classical endocytic regulators but also pathways related to ion and water transport. Notably, NP association and release were highly sensitive to the extracellular fluid environment within the physiological range. By testing inhibitors of these pathways, we identified molecules that reduce NP-cell association and promote release. We further compared common NPs found in human samples and widely used in research: polystyrene (PS), polyethylene (PE), and polypropylene (PP). Although these NPs similarly impaired proliferation and motility, they showed markedly different cellular association and release dynamics. These findings reveal the impact of NPs on tissue cell functions and uncover novel regulatory pathways, establishing a quantitative framework for studying NP-cell interactions in biologically relevant conditions.

cell biology↗

bioRxiv2026

Monocytes are biological sensors of aging and frailty in humans

Among older adults, frailty is clinically identifiable and characterized by increased vulnerability to adverse health outcomes. Although various tools exist to identify frailty, diagnosis often depends on late-stage clinical symptoms, which typically limit proactive intervention options. We considered whether aging and frailty information may be encoded in the single-cell behaviors and dynamic responses of primary human monocytes. Combining high-content imaging, single-cell behavior profiling, and machine learning, we demonstrated unique age- and frailty-dependent monocyte behaviors at baseline and following exposure to inflammatory stressors. Using these single-cell behaviors, we developed a deep learning neural network model called scTRAIT. scTRAIT accurately predicts the frailty status of older donors, including the capability to track and forecast longitudinal changes in frailty status. Collectively, these findings demonstrate that aging and frailty information are robustly encoded within single-cell behaviors, establishing monocytes as significant biological sensors of aging and frailty in humans. TeaserSingle-cell monocyte responses enable robust prediction of aging and frailty in humans

bioengineering↗

bioRxiv2026

Acute priming using elevated fluid viscosity recovers young-like single-cellsurveillance behaviors in aged human T cells

Aging is a complex biological process, often characterized by increased vulnerability to disease, infection, and death. This increased vulnerability is mechanistically linked to a progressive and functional decline of the immune system. In humans, aged lymphocytes lose their capacity to effectively surveil within diverse microenvironments, decreasing their capability for clearing infections and maintaining physiological homeostasis. However, specific mechanisms by which aged lymphocytes, specifically T cells, lose this capacity to surveil remain unclear. We profiled three core characteristics of T cell surveillance at single-cell resolution, specifically migration, deformability, and sensing. While aged T cells retained their capacity for spontaneous migration, they exhibited impaired cellular deformability and deficiencies in sensing local signaling cues. To modulate this surveillance defect, we performed mechanical reprogramming using elevated fluid viscosity. Results showed that acute priming of aged T cells with elevated fluid viscosity recovered a transient young-like surveillance phenotype, which was mechanistically linked to membrane tension, cortical F-actin, and Arp3 expression. These findings reveal a key source of surveillance defects in aged T cells and provide an effective mechanical approach to tuning their single-cell behaviors. TeaserRecovery of young-like surveillance phenotypes in aging human T cells via viscosity priming

bioengineering↗

bioRxiv2025

Data-driven simulations elucidate how lymphocyte motility behaviors drive cell-cell interactions within germinal centers

Lymphocytes rely on cell motility to surveil immune microenvironments and engage in contact-mediated interactions with other cells as part of the adaptive immune response. Within the germinal center (GC) light zone, germinal center B-cells (GCBs) and T-follicular helper cells (Tfhs) engage in cell-cell interactions that enable antibody affinity maturation. The number and duration of GCB-Tfh interactions correlate with the success of the germinal center in effectively generating antibodies that can bind and neutralize antigens. Prior studies have shown that GCBs and Tfhs exploit distinct motility patterns to surveil the GC light zone and engage in these cell-cell interactions. However, the quantitative relationship between lymphocyte motility parameters (such as speed and tortuosity) and GCB-Tfh interactions has not been systematically explored. Here, we analyzed single-cell trajectories of GCBs and Tfhs from two-photon intravital microscopy videos of GCs within mouse popliteal lymph nodes. We found that these cells exhibit seven distinct motility behaviors, each with characteristic speeds and tortuosities. GCBs tended to move in slow and tortuous paths, while Tfhs adopted faster and more directed trajectories. We then developed a three-dimensional agent-based model (ABM) to simulate these experimentally-observed GCB and Tfh motility behaviors and predict their impact on GCB-Tfh interactions. Using the ABM, we found that the baseline motility behaviors of GCBs and Tfhs allow GCBs to maximize interactions with distinct Tfhs in a confined space.

systems biology↗

bioRxiv2024

Self-organizing ovarian somatic organoids preserve cellular heterogeneity and reveal cellular contributions to ovarian aging

Ovarian somatic cells are essential for reproductive function, but no existing ex vivo models recapitulate the cellular heterogeneity or interactions within this compartment. We engineered a novel ovarian somatic organoid model by culturing a stroma-enriched fraction of mouse ovaries in scaffold-free agarose micromolds. Ovarian somatic organoids self-organized, maintained diverse cell populations, produced extracellular matrix, and secreted hormones. Organoids generated from reproductively old mice exhibited reduced aggregation and growth compared to young counterparts, as well as differences in cellular composition. Interestingly, matrix fibroblasts from old mice demonstrated upregulation of pathways associated with the actin cytoskeleton and downregulation of cell adhesion pathways, indicative of increased cellular stiffness which may impair organoid aggregation. Cellular morphology, which is regulated by the cytoskeleton, significantly changed with age and in response to actin depolymerization. Moreover, actin depolymerization rescued age-associated organoid aggregation deficiency. Overall, ovarian somatic organoids have advanced fundamental knowledge of cellular contributions to ovarian aging.

cell biology↗

bioRxiv2024

High-motility pro-tumorigenic monocytes drive macrophage enrichment in the tumor microenvironment

Enrichment of tumor-associated macrophages (TAM{Phi}s) in the tumor microenvironment correlates with worse clinical outcomes in triple-negative breast cancer (TNBC) patients, prompting the development of therapies to inhibit TAM{Phi} infiltration. However, the lackluster efficacy of CCL2-based chemotaxis blockade in clinical trials suggests that a new understanding of monocyte/macrophage infiltration may be necessary. Here we demonstrate that random migration, and not only chemotaxis, drives macrophage tumor infiltration. We identified tumor- associated monocytes (TAMos) that display a dramatically enhanced migration capability, induced rapidly by the tumor microenvironment, that drives effective tumor infiltration, in contrast to low-motility differentiated macrophages. TAMo, not TAM{Phi}, promotes cancer cell proliferation through activation of the MAPK pathway. IL-6 secreted both by cancer cells and TAMo themselves enhances TAMo migration by increasing dendritic protrusion dynamics and myosin- based contractility via the JAK2/STAT3 signaling pathway. Independent from CCL2 mediated chemotaxis, IL-6 driven enhanced migration and pro-proliferative effect of TAMo were validated in a syngeneic TNBC mouse model. Depletion of IL-6 in cancer cells significantly attenuated monocyte infiltration and reversed TAMo-induced cancer cell proliferation. This work reveals the critical role random migration plays in monocyte driven TAM{Phi} enrichment in a tumor and pinpoints IL-6 as a potential therapeutic target in combination with CCL2 to ameliorate current strategies against TAM{Phi} infiltration.

immunology↗

bioRxiv2024

Single-cell morphology encodes functional subtypes of senescence in aging human dermal fibroblasts

Cellular senescence is an established driver of aging, exhibiting context-dependent phenotypes across multiple biological length-scales. Despite its mechanistic importance, profiling senescence within cell populations is challenging. This is in part due to the limitations of current biomarkers to robustly identify senescent cells across biological settings, and the heterogeneous, non-binary phenotypes exhibited by senescent cells. Using a panel of primary dermal fibroblasts, we combined live single-cell imaging, machine learning, multiple senescence induction conditions, and multiple protein-based senescence biomarkers to show the emergence of functional subtypes of senescence. Leveraging single-cell morphologies, we defined eleven distinct morphology clusters, with the abundance of cells in each cluster being dependent on the mode of senescence induction, the time post-induction, and the age of the donor. Of these eleven clusters, we identified three bona-fide senescence subtypes (C7, C10, C11), with C10 showing the strongest age-dependence across a cohort of fifty aging individuals. To determine the functional significance of these senescence subtypes, we profiled their responses to senotherapies, specifically focusing on Dasatinib + Quercetin (D+Q). Results indicated subtype-dependent responses, with senescent cells in C7 being most responsive to D+Q. Altogether, we provide a robust single-cell framework to identify and classify functional senescence subtypes with applications for next-generation senotherapy screens, and the potential to explain heterogeneous senescence phenotypes across biological settings based on the presence and abundance of distinct senescence subtypes.

bioengineering↗

bioRxiv2024

Substrate stiffness modulates the emergence and magnitude of senescence phenotypes

Cellular senescence is a major driver of aging and disease. Here we show that substrate stiffness modulates the emergence and magnitude of senescence phenotypes after exposure to senescence inducers. Using a primary dermal fibroblast model, we show that decreased substrate stiffness accelerates senescence-associated cell-cycle arrest and regulates the expression of conventional protein-based biomarkers of senescence. We found that the expression of these senescence biomarkers, namely p21WAF1/CIP1 and p16INK4a are mechanosensitive and are in-part regulated by myosin contractility through focal adhesion kinase (FAK)-ROCK signaling. Interestingly, at the protein level senescence-induced dermal fibroblasts on soft substrates (0.5 kPa) do not express p21WAF1/CIP1 and p16INK4a at comparable levels to induced cells on stiff substrates (4GPa). However, cells express CDKN1a, CDKN2a, and IL6 at the RNA level across both stiff and soft substrates. Moreover, when cells are transferred from soft to stiff substrates, senescent cells recover an elevated expression of p21WAF1/CIP1 and p16INK4a at levels comparable to senescence cells on stiff substrates, pointing to a mechanosensitive regulation of the senescence phenotype. Together, our results indicate that the emergent senescence phenotype depends critically on the local mechanical environments of cells and that senescent cells actively respond to changing mechanical cues.

molecular biology↗

bioRxiv2024

Geometric changes in the nucleoids of Deinococcus radiodurans reveal involvement of new proteins in recovery from ionizing radiation.

The extremophile Deinococcus radiodurans maintains a highly-organized and condensed nucleoid as its default state, possibly contributing to high tolerance of ionizing radiation (IR). Previous studies of the D. radiodurans nucleoid were limited by reliance on manual image annotation and qualitative metrics. Here, we introduce a high-throughput approach to quantify the geometric properties of cells and nucleoids, using confocal microscopy, digital reconstructions of cells, and computational modeling. We utilize this novel approach to investigate the dynamic process of nucleoid condensation in response to IR stress. Our quantitative analysis reveals that at the population level, exposure to IR induced nucleoid compaction and decreased size of D. radiodurans cells. Morphological analysis and clustering identified six distinct sub-populations across all tested experimental conditions. Results indicate that exposure to IR induces fractional redistributions of cells across sub-populations to exhibit morphologies that associate with greater nucleoid condensation, and decreased abundance of sub-populations associated with cell division. Nucleoid associated proteins (NAPs) may link nucleoid compaction and stress tolerance, but their roles in regulating compaction in D. radiodurans is unknown. Imaging of genomic mutants of known and suspected NAPs that contribute to nucleoid condensation found that deletion of nucleic acid binding proteins, not previously described as NAPs, can remodel the nucleoid by driving condensation or decondensation in the absence of stress and that IR increases the abundance of these morphological states. Thus, our integrated analysis introduces a new methodology for studying environmental influences on bacterial nucleoids and provides an opportunity to further investigate potential regulators of nucleoid condensation. ImportanceD. radiodurans, an extremophile known for its stress tolerance, constitutively maintains a highly-condensed nucleoid. Qualitative studies have described nucleoid behavior under a variety of conditions. However, a lack of quantitative data regarding nucleoid organization and dynamics have limited our understanding of regulatory mechanisms controlling nucleoid organization in D. radiodurans. Here, we introduce a quantitative approach that enables high-throughput quantitative measurements of subcellular spatial characteristics in bacterial cells. Applying this to wild-type or single-protein-deficient populations of D. radiodurans subjected to ionizing radiation, we identified significant stress-responsive changes in cell shape, nucleoid organization, and morphology. These findings highlight this methodologys adaptability and capacity for quantitatively analyzing the cellular response to stressors for screening cellular proteins involved in bacterial nucleoid organization.

molecular biology↗

bioRxiv2023

Particulate matter composition drives differential molecular and morphological responses in lung epithelial cells

Particulate matter (PM) is a ubiquitous component of indoor and outdoor air pollution that is epidemiologically linked to many human pulmonary diseases. PM has many emission sources, making it challenging to understand the biological effects of exposure due to the high variance in chemical composition. However, the effects of compositionally unique particulate matter mixtures on cells have not been analyzed using both biophysical and biomolecular approaches. Here, we show that in a human bronchial epithelial cell model (BEAS-2B), exposure to three chemically distinct PM mixtures drives unique cell viability patterns, transcriptional remodeling, and the emergence of distinct morphological subtypes. Specifically, PM mixtures modulate cell viability and DNA damage responses and induce the remodeling of gene expression associated with cell morphology, extracellular matrix organization and structure, and cellular motility. Profiling cellular responses showed that cell morphologies change in a PM composition-dependent manner. Lastly, we observed that particulate matter mixtures with high contents of heavy metals, such as cadmium and lead, induced larger drops in viability, increased DNA damage, and drove a redistribution among morphological subtypes. Our results demonstrate that quantitative measurement of cellular morphology provides a robust approach to gauge the effects of environmental stressors on biological systems and determine cellular susceptibilities to pollution.

systems biology↗

bioRxiv2022

Profiling emergent behaviors from single-cell motility

Cell motility plays an essential role in many biological processes as cells move and interact within their local microenvironments. Current methods for quantifying cell motility typically involve tracking individual cells over time, but the results are often presented as averaged values across cell populations. While informative, these ensemble approaches have limitations in assessing cellular heterogeneity and identifying generalizable patterns of single-cell behaviors, at baseline and in response to perturbations. In this study, we introduce CaMI, a computational framework designed to leverage the single-cell nature of motility data. CaMI identifies and classifies distinct spatio-temporal behaviors of individual cells, enabling robust classification of single-cell motility patterns in a large dataset (n=74,253 cells). This framework allows quantification of spatial and temporal heterogeneities, determination of single-cell motility behaviors across various biological conditions, and provides a visualization scheme for direct interpretation of dynamic cell behaviors. Importantly, CaMI reveals insights that conventional cell motility analyses may overlook, showcasing its utility in uncovering robust biological insights. Together, we present a multivariate framework to classify emergent patterns of single-cell motility, emphasizing the critical role of cellular heterogeneity in shaping cell behaviors across populations. TeaserA computational framework to identify and classify single-cell motility patterns and phenotypic heterogeneity across biological conditions.

bioengineering↗

bioRxiv2021

Senescent stroma induces nuclear deformations in cancer cells via the inhibition of RhoA/ROCK/myosin II-based cytoskeletal tension

The presence of senescent cells within tissues has been functionally linked to malignant transformations. Here, using tension-gauge tethers technology, particle-tracking microrheology, and quantitative microscopy, we demonstrate that senescent associated secretory phenotype (SASP) derived from senescent fibroblasts impose nuclear lobulations and volume shrinkage on malignant cells, which stems from the loss of RhoA/ROCK/myosin II-based cortical tension. This loss in cytoskeletal tension induces decreased cellular contractility, adhesion, and increased mechanical compliance. These SASP-induced morphological changes are in part mediated by lamin A/C. These findings suggest that SASP induces a defective outside-in mechanotransduction, from actomyosin fibers in the cytoplasm to the nuclear lamina, thereby triggering a cascade of biophysical and biomolecular changes in cells that associate with malignant transformations.

cancer biology↗

bioRxiv2020

Deep Learning Identification of Stiffness Markers in Breast Cancer

While essential to our understanding of solid tumor progression, the study of cell and tissue mechanics has yet to find traction in the clinic. Determining tissue stiffness, a mechanical property known to promote a malignant phenotype in vitro and in vivo, is not part of the standard algorithm for the diagnosis and treatment of breast cancer. Instead, clinicians routinely use mammograms to identify malignant lesions and radiographically dense breast tissue is associated with an increased risk of developing cancer. Whether breast density is related to tumor tissue stiffness, and what cellular and non-cellular components of the tumor contribute the most to its stiffness are not well understood. Through training of a deep learning network and mechanical measurements of fresh patient tissue, we create a bridge in understanding between clinical and mechanical markers. The automatic identification of cellular and extracellular features from hematoxylin and eosin (H&E)-stained slides reveals that global and local breast tissue stiffness best correlate with the percentage of straight collagen. Global breast tissue mechanics correlate weakly with the percentage of blood vessels and fibrotic tissue, and non-significantly with the percentage of fat, ducts, tumor cells, and wavy collagen in tissue. Importantly, the percentage of dense breast tissue does not directly correlate with tissue stiffness or straight collagen content.

cancer biology↗

bioRxiv2020

HSP90 facilitates oncogenic alterations of metabolism in B-cell lymphomas

HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here, we described a novel role of HSP90 in the cytosolic compartmentalization of metabolic pathways in proliferating cancer cells. We found that HSP90 assists in the organization of metabolic enzymes into non-membrane-bound functional compartments termed metabosomes. Under experimental conditions that conserved the cellular proteostasis, we demonstrated that the compartmentalizing activity of HSP90 is critical to sustain the coordinated synthesis of multiple metabolites required for energy production, maintenance of the cellular biomass and secretion of immunometabolites. Conversely, inhibition of the nucleating capacity of HSP90 modified the topology of cytosolic metabosomes before protein degradation was apparent decreasing the efficiency of MYC-driven metabolic pathways. Inhibition of HSP90 decreases cancer metabolism in B-cell lymphoma cells and patients providing a novel mechanism of activity for this class of drugs.

cancer biology↗