Biology subjects

Bailey, K. M.

Publications and source records attributed to Bailey, K. M..

6 recordsLinked to original sources

bioRxiv2025

Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma

Sub-populations of cancer-associated fibroblast (CAF)-like tumor cells deposit extracellular matrix (ECM) proteins that support Ewing sarcoma (EwS) progression and metastasis. We previously showed a hallmark of CAF-like EwS cells is their hybrid transcriptional state wherein the driver fusion oncogene, EWS::FLI1, maintains activation of proliferative programs but loses capacity to repress mesenchymal genes. Here, we studied primary patient tumors and cell line models to identify molecular drivers of this hybrid state. Our data reveal that hybrid EwS cells are induced and maintained by a TGF{beta} signaling positive feedback loop. Hybrid cells de-repress TGFBR2 and upregulate expression and secretion of TGF{beta}2 to sustain pathway activation and ECM deposition. While TGF{beta} ligands can potently induce growth arrest in cells of epithelial origin, we show that TGF{beta}1 and TGF{beta}2 promote cell invasion of EwS cells without affecting proliferation. Thus, stroma and tumor-derived TGF{beta} ligands induce and maintain hybrid EwS cells to promote pro-metastatic cell phenotypes.

cancer biology↗

bioRxiv2025

SARC028 samples reveal an interplay between TGF-beta, interferon signaling and low HLA class I expression as contributors to Ewing sarcoma checkpoint blockade resistance

PurposeEwing sarcoma, in contrast to some adult sarcoma subtypes, generally does not respond to single agent immunotherapy targeting PD1. The features of Ewing sarcoma that preclude the effectiveness of immunotherapy remain largely unknown. To address this question, we utilized biopsies from patients with Ewing sarcoma obtained pre- and post-pembrolizumab (anti-PD1) therapy from the phase 2 clinical trial SARC028 to interrogate the Ewing tumor microenvironment and features associated with resistance to checkpoint inhibition. Experimental DesignWe utilize multiplexed immunofluorescence, spatial proteomics and spatial transcriptomics to analyze paired pre- and 8 weeks post-treatment biopsy specimens from patients with Ewing sarcoma enrolled on SARC028. ResultsPembrolizumab therapy did not alter the quantity of immune cell infiltration in Ewing tumor biopsies. Analysis of tumor-associated protein markers revealed increased immunoregulatory markers after pembrolizumab. Spatial transcriptomics identified ten cellular neighborhoods (CN) across patients consisting of specific cell subsets. CN10 was consistently observed across patients with poor response. This cellular neighborhood was enriched for a tumor subpopulation with high TGF-{beta} response, low interferon (IFN) response, and low HLA class I expression. IFN response, HLA class I expression, and overall immune infiltration were correlated. ConclusionsAnalyses of the tumor microenvironment from Ewing sarcoma biopsies reveals an immunosuppressive triad, the disruption of which should be pursued to improve antitumor immunity. This work highlights the unique insight that can be gained from the analysis of paired patient Ewing sarcoma tumor biopsy samples from clinical trials. Statement of translational relevanceSingle agent checkpoint inhibitors have demonstrated limited clinical benefit in bone sarcomas, including Ewing sarcoma (EwS). While in vitro and limited patient tumor analyses have suggested mechanisms of immunotherapy resistance in EwS, tumor biopsies following checkpoint inhibitor administration have not been examined. SARC028 was a phase II study investigating blockade of programmed cell death-1 (PD-1) in patients with relapsed/refractory sarcomas, including EwS. Tumor biopsies were collected prior to and 8 weeks after anti-PD1 therapy. Here, we leverage a unique opportunity to understand EwS immunotherapy resistance through analysis of paired tumor samples from SARC028. Using a multi-omics approach, we identify features of EwS that contribute to primary resistance to anti-PD1 including TGF-{beta}, reduced interferon signaling and low HLA class I expression. This study provides an improved understanding of tumor characteristics driving poor response to immunotherapy in relapsed EwS and will guide the development of future trials to modulate this immunosuppressive axis.

cancer biology↗

bioRxiv2024

Immunocompetent murine model of Ewing sarcoma reveals role for TGFβ inhibition to enhance immune infiltrates in Ewing tumors during radiation

Ewing sarcoma (ES) is an aggressive cancer diagnosed in adolescents and young adults. The fusion oncoprotein (EWSR1::FLI1) that drives Ewing sarcoma is known to downregulate TGFBR2 expression (part of the TGF{beta} receptor). Because TGFBR2 is downregulated, it was thought that TGF{beta} likely plays an inconsequential role in Ewing biology. However, the expression of TGF{beta} in the Ewing tumor immune microenvironment (TIME) and functional impact of TGF{beta} in the TIME remains largely unknown given the historical lack of immunocompetent preclinical models. Here, we use single-cell RNAseq analysis of human Ewing tumors to show that immune cells, such as NK cells, are the largest source of TGF{beta} production in human Ewing tumors. We develop a humanized (immunocompetent) mouse model of ES and demonstrate distinct TME signatures and metastatic potential in these models as compared to tumors developed in immunodeficient mice. Using this humanized model, we study the effect of TGF{beta} inhibition on the Ewing TME during radiation therapy, a treatment that both enhances TGF{beta} activation and is used to treat aggressive ES. Utilizing a trivalent ligand TGF{beta} TRAP to inhibit TGF{beta}, we demonstrate that in combination with radiation, TGF{beta} inhibition both increases ES immune cell infiltration and decreases lung metastatic burden in vivo. The culmination of these data demonstrates the value of humanized models to address immunobiologic preclinical questions in Ewing sarcoma and suggests TGF{beta} inhibition as a promising intervention during radiation therapy to promote metastatic tumor control.

cancer biology↗

bioRxiv2023

Decoding familiar visual object categories in the mu rhythm oscillatory response

Whilst previous research has linked attenuation of the mu rhythm to the observation of specific visual categories, and even to a potential role in action observation via a putative mirror neuron system, much of this work has not considered what specific type of information might be coded in this oscillatory response when triggered via vision. Here, we sought to determine whether the mu rhythm contains content-specific information about the identity of familiar (and also unfamiliar) graspable objects. In the present study, right-handed participants (N=27) viewed images of both familiar (apple, wine glass) and unfamiliar (cubie, smoothie) graspable objects, whilst performing an orthogonal task at fixation. Multivariate pattern analysis (MVPA) revealed significant decoding of familiar, but not unfamiliar, visual object categories in the mu rhythm response. Thus, simply viewing familiar graspable objects may automatically trigger activation of associated tactile and/or motor properties in sensorimotor areas, reflected in the mu rhythm. In addition, we report significant attenuation in the central beta band for both familiar and unfamiliar visual objects, but not in the mu rhythm. Our findings highlight how analysing two different aspects of the oscillatory response - either attenuation or the representation of information content - provide complementary views on the role of the mu rhythm in response to viewing graspable object categories. HighlightsO_LIThe Mu Rhythm oscillation contains fine-grained information about the identity of familiar, graspable objects (but not unfamiliar) C_LIO_LIThis study offers evidence of a possible oscillatory marker for cross-sensory effects involving sensorimotor and visual cortices C_LIO_LIDifferent analysis techniques (univariate vs multivariate) imply different conclusions about the role of specific oscillations in the perception of graspable objects C_LIO_LIThe alpha rhythm at occipital sites shows greater attenuation for unfamiliar objects but better representation for familiar objects consistent with sharpening accounts of Predictive Processing C_LI

neuroscience↗

bioRxiv2020

PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways

Ewing sarcoma, an oncofusion-driven primary bone tumor, can occur in the setting of various germline mutations in DNA damage repair pathway genes. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. PARP inhibitors (PARPi) are effective against Ewing sarcoma cells in vitro, though have demonstrated limited success in clinical trials to date. In order to assess the impact of BARD1 loss on Ewing sarcoma sensitivity to PARP inhibitor therapy, we generated the novel PSaRC318 patient-derived Ewing tumor cell from our patient with a germline BARD1 mutation and then analyzed the response of these cells to PARPi. We demonstrate that PSaRC318 cells are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that loss of BARD1 enhances PARPi sensitivity. In certain malignancies, DNA damage can activate the IRF1 (interferon response factor 1) immunoregulatory pathway, and the activation of this pathway can drive immunosuppression through upregulation of the immune checkpoint protein PD-L1. In order to determine the ability of PARPi to alter Ewing tumor immunoregulation, we evaluated whether PARPi results in upregulation of the IRF1-PDL1 pathway. Indeed, we now demonstrate that PARPi leads to increased PD-L1 expression in Ewing sarcoma. Together, these data thus far suggest that while Ewing tumors harboring germline mutations in DNA damage repair proteins may in respond to PARPi in vitro, in vivo benefit of PARPi may only be demonstrated when counteracting the immunosuppressive effects of DNA damage by concurrently targeting immune checkpoint proteins.

cancer biology↗

bioRxiv2019

Decoding the sound of hand-object interactions in primary somatosensory cortex

Neurons, even in earliest sensory regions of cortex, are subject to a great deal of contextual influences from both within and across modality connections. Recent work has shown that primary sensory areas can respond to and in some cases discriminate stimuli not of their target modality: for example, primary somatosensory cortex (SI) discriminates visual images of graspable objects. In the present work, we investigated whether SI would discriminate sounds depicting hand-object interactions (e.g. bouncing a ball). In a rapid event-related functional magnetic resonance imaging (fMRI) experiment, participants listened attentively to sounds from three categories: hand-object interactions, and control categories of pure tones and animal vocalizations, while performing a one-back repetition detection task. Multi-voxel pattern analysis revealed significant decoding of different hand-object interactions within SI, but not for either control category. Crucially, in the hand-sensitive voxels defined from an independent tactile localizer, decoding accuracies were significantly higher for hand-object interactions compared to pure tones in left SI. Our findings indicate that simply hearing sounds depicting familiar hand-object interactions elicit different patterns of activity in SI, despite the complete absence of tactile stimulation. These results highlight the rich information that can be transmitted across sensory modalities even to primary sensory areas.

neuroscience↗