Biology subjects

Suita, Y.

Publications and source records attributed to Suita, Y..

6 recordsLinked to original sources

bioRxiv2026

Intratumoral B7H3:CD3 Bispecific T-cell Engager Drives Localized T-cell Accumulation in Canine Sarcoma Patients

BackgroundBispecific T-cell Engagers (TCEs) targeting B7H3 (CD276) show promise for solid tumors but are limited by systemic toxicities and poor tumor penetration. Intratumoral (IT) delivery is proposed as a solution, but the safety and spatial pharmacodynamics (PD) remain poorly defined in these malignancies. Spontaneous canine tumors serve as a highly translatable model for human therapeutic development due to its clinical, genetic, and immunological similarities to human patients. This study evaluates the feasibility of an IT-delivered B7H3:CD3 TCE in a trial that enrolls companion dogs with solid tumors. MethodsWe engineered a canine B7H3:CD3 TCE and validated its ability to induce T-cell activation and T-cell mediated cytotoxicity in vitro on several B7H3-expressing canine tumor cell lines. Two STS canine patients received intratumoral columnar injections of the TCE and saline (internal control) at fixed distance of 1.5cm using a custom-engineered multi-needle assembly. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. PD response was analyzed by H&E and immunohistochemistry. ResultsIn vitro assays validated the cytotoxicity of the B7H3:CD3 TCE on B7H3+ canine tumor cell lines. TCE IT administration (7.83 g / 148.2 pmol) was well tolerated with no adverse events greater than Grade 1 and no evidence of systemic cytokine release or organ toxicity. Immunohistochemistry of tumors collected 7 days after TCE administration revealed a significant five-fold increase in CD3+ T-cell density at the TCE injection site (within 0.5 cm radius) compared to internal saline controls. ConclusionsThis study demonstrated the feasibility of evaluating pharmacodynamic response to IT delivery of B7H3:CD3 TCE, namely local T-cell accumulation. T-cell localization around the TCE injection site supports our hypothesis that effective IT immunotherapy might require enhanced volumetric coverage using multi-needle injections and/or co-stimulatory strategies to convert T-cell localization into a robust, sustained anti-tumor response.

immunology↗

bioRxiv2024

Machine learning on multiple epigenetic features reveals H3K27Ac as a driver of gene expression prediction across patients with glioblastoma.

Cancer cells show remarkable plasticity and can switch lineages in response to the tumor microenvironment. Cellular plasticity drives invasiveness and metastasis and helps cancer cells to evade therapy by developing resistance to radiation and cytotoxic chemotherapy. Increased understanding of cell fate determination through epigenetic reprogramming is critical to discover how cancer cells achieve transcriptomic and phenotypic plasticity. Glioblastoma is a perfect example of cancer evolution where cells retain an inherent level of plasticity through activation or maintenance of progenitor developmental programs. However, the principles governing epigenetic drivers of cellular plasticity in glioblastoma remain poorly understood. Here, using machine learning (ML) we employ cross-patient prediction of transcript expression using a combination of epigenetic features (ATAC-seq, CTCF ChIP-seq, RNAPII ChIP-seq, H3K27Ac ChIP-seq, and RNA-seq) of glioblastoma stem cells (GSCs). We investigate different ML and deep learning (DL) models for this task and build our final pipeline using XGBoost. The model trained on one patient generalizes to another one suggesting that the epigenetic signals governing gene transcription are consistent across patients even if GSCs can be very different. We demonstrate that H3K27Ac is the epigenetic feature providing the most significant contribution to cross-patient prediction of gene expression. In addition, using H3K27Ac signals from patients-derived GSCs, we can predict gene expression of human neural crest stem cells suggesting a shared developmental epigenetic trajectory between subpopulations of these malignant and benign stem cells. Our cross-patient ML/DL models determine weighted patterns of influence of epigenetic marks on gene expression across patients with glioblastoma and between GSCs and neural crest stem cells. We propose that broader application of this analysis could reshape our view of glioblastoma tumor evolution and inform the design of new epigenetic targeting therapies.

cancer biology↗

bioRxiv2023

MITF regulates IDH1 and NNT and drives a transcriptional program protecting cutaneous melanoma from reactive oxygen species

Microphthalmia-associated transcription factor (MITF) plays pivotal roles in melanocyte development, function, and melanoma pathogenesis. MITF amplification occurs in melanoma and has been associated with resistance to targeted therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo. Some of the MITF target genes involved, such as IDH1 and NNT, are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state. One Sentence SummaryMITF promote melanoma survival via increasing ROS tolerance.

cancer biology↗

bioRxiv2023

Engineering GliaTrap: a biodegradable non-swelling hydrogel with tuned release of CXCL12 to attract migrating glioblastoma cells

Glioblastoma is the most aggressive type of brain cancer with an average overall survival of 15-21 months after first diagnosis. The relapse is mainly caused by migrating glioblastoma cells that diffuse away from the tumor mass into the brain parenchyma and retain cancer stem cell (GSC) properties. Current therapeutic options are ineffective and inevitably result in relapse, indicating a high unmet medical need for innovative therapies in the treatment of invasive glioblastoma. To address this challenge, we propose a new therapeutic modality: GliaTrap, a biodegradable non-swelling, injectable hydrogel with sustained release of a chemoattractant for GSCs that lures and traps the migrating cells back to the tumor resection cavity. We developed a biodegradable and injectable hyaluronan/collagen II-based (HA/Col) hydrogel that does not swell in vivo. The hydrogel is embedded with CXCL12 loaded liposomes and is tuned for sustained release of CXCL12. The safety profile of liposome-embedded HA/Col hydrogel was determined in-vivo after stereotactic implantation in the mouse brain. The efficacy of GliaTrap to attract GSCs was determined ex vivo using a 3D tumor spheroid model and in-vivo using 3D light-sheet microscopy in orthotopic human glioblastoma xenografts. Our findings suggest that GliaTrap could represent a safe and efficacious new therapeutic approach for glioblastoma and potentially serve as a drug delivery platform to locally deliver tumor-killing agents. One Sentence SummaryGliaTrap is a biodegradable non-swelling hydrogel with tuned release of a chemoattractant to attract invading glioma cells and serve as delivery platform for local therapeutics.

cancer biology↗

bioRxiv2022

The germline factor DDX4 contributes to the chemoresistance of small cell lung cancer cells

Human cancers often re-express germline factors, yet their mechanistic role in oncogenesis and cancer progression remains unknown. Here we demonstrate that DDX4, a germline factor and RNA helicase conserved in all multicellular organisms, contributes to epithelial mesenchyme transition (EMT)-like features and cisplatin resistance in small cell lung cancer (SCLC) cells. DDX4 depletion in H69AR and SHP77 cell lines decreased motility and resistance to cisplatin, whereas its overexpression increased these features. Proteomic analysis suggests that DDX4 upregulates metabolic protein expression related to DNA repair and immune/inflammatory response, suggesting its fundamental function may be in regulating cellular metabolism. Consistent with these trends in cell lines, DDX4 depletion compromised in vivo tumor development while its overexpression enhanced tumor growth even after cisplatin treatment in nude mice. Although the DDX4 expression level in somatic tumors is generally low compared to that in the germline, the relatively higher DDX4 expression in SCLC patients correlates with decreased survival and shows increased expression of EMT and cisplatin resistance markers. Taken together, we conclude that DDX4 influences the survival of SCLC patients by altering cellular metabolism in response to environmental cues such as drug treatments. This fundamental function of DDX4 as a germline factor might be applicable in other cancer types that express DDX4 and may serve as a key to combat specific tumors that are highly resistant to treatments. HighlightsO_LIDDX4 contributes to cellular motility and drug resistance in SCLC cells. C_LIO_LIDDX4-overexpression globally alters the proteome and suppresses cytokine production. C_LIO_LIDDX4 promotes tumorigenesis and drug resistance in vitro and in vivo. C_LIO_LIDDX4 expression correlates with survival in SCLC patients and with immune/inflammatory response both in cell lines and patient samples. C_LI

cancer biology↗

bioRxiv2017

OCT4 Impedes Cell Fate Redirection By The Melanocyte Lineage Master Regulator MITF

Ectopic expression of lineage master regulators induces transdifferentiation. Whether cell fate transitions can be induced during various developmental stages has never been systemically examined. Here we discovered that amongst different developmental stages, embryonic stem cells (ESCs) were resistant to cell fate conversion induced by the melanocyte lineage master regulator MITF. We generated a transgenic system and found that in ESCs, the pluripotency master regulator, OCT4, counteracts pro-differentiation induced by MITF by physical interference with MITF transcriptional activity. We further found that ESCs must be released from OCT4-maintained pluripotency prior to ectopically induced differentiation. Moreover, OCT4 induction in various differentiated cells repressed their lineage identity in vivo. Alongside, chromatin architecture combined with ChIP-seq analysis suggested that OCT4 competes with various lineage master regulators for binding promoters and enhancers. Our analysis reveals pluripotency and transdifferentiation regulatory principles and could open new opportunities in the field of regenerative medicine.

developmental biology↗