Biology subjects

Bais, M. V.

Publications and source records attributed to Bais, M. V..

6 recordsLinked to original sources

bioRxiv2025

Dietary Serine Restriction Impacts H3K27 and H3K4 Methyl Epigenomes to Impede Head and Neck Cancer Cell Plasticity and Tumor Growth

Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy characterized by high morbidity, therapeutic resistance and intratumoral heterogeneity driven by plastic cell states. Given that metabolic inputs can shape cell identities via epigenetic mechanisms, we investigated how metabolism of a non-essential amino acid, serine, affects histone modifications with key roles in cell plasticity: H3K27me3, which represses differentiation genes, and H3K4me3 which activates stemness and epithelial-to-mesenchymal transition (EMT) genes. Using a panel of human OSCC patient-derived cell lines and an orthotopic murine isograft model, we show that OSCC cells depend on exogenous serine for proliferation. Dietary serine deprivation induced de novo serine synthesis with a concomitant increase in -ketoglutarate (KG), a cofactor for KDM6B and KDM5A/B demethylases of H3K27me3 and H3K4me3, respectively. RNA-seq-derived serine deprivation gene signatures revealed activation of keratinization program and suppression of EMT and proliferation genes and tracked with good OSCC patient outcomes in TCGA. Furthermore, CUT & RUN profiling showed site-specific losses of H3K27me3 at differentiation genes and reduction of H3K4me3 at stemness, EMT and cell cycle genes. However, inhibition of KG with 2-hydroxyglutarate was not sufficient to rescue cell proliferation. Instead, genome-wide analysis revealed widespread H3K27me3-H3K4me3 bivalency, with extensive transcriptional repression of proliferation and oncogenic programs. Functionally, serine deprivation impaired orthotopic tumor growth and improved the immune landscape in syngeneic mice. Our studies identify a metabolic serine-KG-KDM-H3K27me3/H3K4me3 bivalency axis that globally reprograms OSCC chromatin as a potential therapeutic strategy to impede tumor plasticity and evolution to advanced disease. ImplicationsThis study identifies the tumor-suppressive role of dietary serine deprivation through epigenetic reprogramming of chromatin in OSCC.

cancer biology↗

bioRxiv2025

A Humanized Mouse Model of Oral Squamous Cell Carcinoma for Investigating Resistance to Anti-PD1 Immunotherapy

Immunotherapy has transformed cancer therapeutics; however, its impact on oral squamous cell carcinoma (OSCC) remains limited due to acquired resistance, including to Pembrolizumab. To better understand this challenge, we develop a humanized mouse model using immune-deficient NCG mice engrafted with human peripheral blood mononuclear cells (hPBMC), followed by orthotopic implantation of head and neck squamous cell carcinoma (HNSCC) stem cells. This model closely mimics the human tumor-immune microenvironment, showing aggressive tumor growth and metastasis. Pembrolizumab treatment significantly decreases CD8+ T cells, dendritic cells, and MHC-class-I expression at tumor sites, which are related to immunotherapy resistance. Further, pembrolizumab treatment confirms the elevated PD-L1 levels, immune evasion pathways and downregulation of MHC-class-I. qPCR further validates human-specific HLA expression. Our model offers a valuable tool for studying immunotherapy resistance and advancing treatment strategies in OSCC and could be useful for other cancers.

cancer biology↗

bioRxiv2025

Unique TMJ-specific transcriptomic signature and its medial layer: Implications in osteoarthritis

ObjectivesOsteoarthritis (OA) is a debilitating joint disease that affects millions of people worldwide, with the temporomandibular joint (TMJ) and knee joint being prominently affected. Despite its prevalence, TMJ-OA remains understudied. This study aimed to investigate the transcriptional signature of the TMJ compared to that of the knee joint and to explore transcriptional differences in the medial and superficial layers of the TMJ-OA. DesignSix-month-old C57BL/6J mice TMJ and knee samples were collected. Goat TMJ superficial and medial layer cartilage was separated and treated with IL-1{beta}. All samples were subjected to bulk RNA sequencing followed by differential expression and gene set enrichment analysis. ResultsWe identified 4,031 protein-coding genes differentially expressed in the TMJ compared to the knee, with significant enrichment of neuronal system genes and lower enrichment of innate immune system genes. Key osteoarthritis biomarkers such as Mmp13, Postn, and Col1a1 were more highly expressed in the TMJ, indicating a higher vulnerability to OA development. IL-1{beta} treatment in goat TMJ chondrocytes mimicked the natural TMJ-OA-like transcriptional changes and immune responses, which are also observed in the rabbit TMJ-OA model. This validated the in vitro goat TMJ-OA model. The IL-1{beta}-treated goat TMJ medial cartilage layer was enriched in OA-associated transcription factors (TFs), senescence genes, and epigenetic regulators. ConclusionOur study demonstrated the unique transcriptomic signature of the TMJ compared with the knee joint, highlighting its vulnerability to OA and pain. These findings provide valuable insights into the molecular mechanisms of TMJ and offer a resource for potential therapeutic target selection for TMJ-OA treatment. HighlightsO_LISignificant enrichment of neuronal system genes and lower enrichment of innate immune system genes in temporomandibular joint. C_LIO_LIKey osteoarthritis biomarkers such as Mmp13, Postn, and Col1a1 have higher expression in temporomandibular joint, indicating a higher vulnerability to osteoarthritis development. C_LIO_LIInterleukin-1beta treatment in goat temporomandibular joint medial layer cartilage mimics natural temporomandibular joint osteoarthritis-like transcriptional changes and immune responses observed in rabbit temporomandibular joint osteoarthritis model. C_LI

molecular biology↗

bioRxiv2025

LOXL2 Deletion Triggers TMJ Osteoarthritis While Overexpression Protects Against NF-κB-Induced Chondrocyte Apoptosis

Temporomandibular joint osteoarthritis (TMJ-OA) affects a significant proportion of the population worldwide. However, there has been no substantial progress in the development of FDA-approved drugs for treatment due to a lack of understanding of the specific factors regulating key TMJ-OA molecular mechanisms. Lysyl Oxidase Like-2 (LOXL2) promotes knee joint cartilage protection, and it is downregulated in TMJ-OA animal model. We evaluated the role of LOXL2 in TMJ cartilage, its molecular mechanism and gene networks using in vivo Loxl2 knockout mice (Acan-Cre; Loxl2flox/flox) and ex vivo goat TMJ cartilage. Our results show that Loxl2 knockout in mice cartilage upregulates Il1b, Mmp9, Mmp13, Adamts4, and Adamts5, whereas it reduces the levels of aggrecan and proteoglycan. Loxl2 deleted TMJ cartilage show a higher enrichment of inflammatory response, TNFA signaling via NF-kB, extracellular matrix (ECM), and collagen degradation pathway network. Conversely, LOXL2 treatment reduces interleukin-1 beta (IL-1{beta})-induced expression of Mmp13, protects mitochondrial function and ECM from degeneration. Importantly, LOXL2 attenuates IL-1{beta}-induced chondrocyte apoptosis via phosphorylation of NF-{kappa}B and expression of pain-related gene PTGS2 (encodes COX2). Taken together, Loxl2 knockout mice exacerbate TMJ-OA through cartilage/ECM degradation, mitochondrial dysfunction, chondrocyte apoptosis, and inflammatory gene expression, whereas LOXL2 treatment mitigates these effects. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/653519v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@cb7540org.highwire.dtl.DTLVardef@17ebe2eorg.highwire.dtl.DTLVardef@1f7fd59org.highwire.dtl.DTLVardef@19fdd7_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

LOXL2 alleviates post-traumatic knee osteoarthritis and pain

Cartilage has limited potential for self-regeneration, and damage can lead to structural, molecular, and functional aberrations, leading to osteoarthritis (OA). Traumatic knee injuries can also lead to cartilage degeneration and post-traumatic OA (PTOA). This study aimed to explore whether lysyl oxidase-like 2 (LOXL2) deletion promotes PTOA-induced transcriptional changes similar to those in human OA, as well as the upregulation of collagen degradation, inflammation, and pain-related gene networks. LOXL2 was found to be downregulated in mouse knee PTOA. Aggrecan promotes specific deletion of Loxl2 in knee cartilage, shows OA-like molecular changes, and aggravates mouse PTOA. Furthermore, transcriptional analysis revealed the upregulation of cartilage degeneration factors, signatures of inflammatory M1 macrophages, and pain. These Loxl2 deleted PTOA mice have a molecular resemblance to the human knee OA pathogenic gene signature, which could lead to OA and pain. Interestingly, intra-articular injection of adenovirus-delivered LOXL2 rescued knee joint function, alleviated cartilage degeneration, restored treadmill-running capabilities, and reduced mechanical allodynia by relieving knee joint disability and pain. Taken together, LOXL2 deletion in mice knee promotes the severity PTOA, similar to human OA, implying its potential as a therapeutic candidate for human PTOA.

molecular biology↗

bioRxiv2025

LSD1 inhibition corrects dysregulated MHC-I and dendritic cells activation through IFNγ-CXCL9-CXCR3 axis to promote antitumor immunity in HNSCC

Poor infiltration of CD8+ T cells and dysregulated MHC-I confer resistance to anticancer clinical therapies. This study aimed to elucidate the mechanisms of lysine-specific demethylase 1 (LSD1, encoded by KDM1A gene) in antitumor immunity in Head and Neck Squamous cell carcinoma (HNSCC). LSD1 inhibition in syngeneic and chronic tobacco carcinogen-induced HNSCC mice recruited activated dendritic cells (DCs), CD4+ and CD8+ T cells, enriched interferon-gamma (IFN{gamma}) in T cells, CXCL9 in DCs, and CXCR3 in T cells, as evaluated using flow cytometry and single-cell RNA-seq analysis. Humanized HNSCC mice and TCGA data validated the inverse correlation of KDM1A with DC markers, CD8+ T cells, and their activating chemokines. Kdm1a knockout in mouse HNSCC and LSD1 inhibitor treatment to co-culture of human HNSCC cells with human peripheral blood mononuclear cells (PBMCs) resulted in MHC-I upregulation in cancer cells for efficient antigen presentation in tumors. Overall, LSD1 inhibition in tumor cells upregulates MHC class I and induces DCs to produce CXCL9, which in turn activates CD8+ T cells through the CXCL9-CXCR3 axis to produce IFN{gamma}. Finally, we identified a novel mechanism by which LSD1 inhibition promotes the activation of H3K4me2 and its direct interaction with MHC-I to induce antitumor immunity. This may have implications in poorly immunogenic and immunotherapy-resistant cancers. Statement of SignificanceLSD1-mediated unique mechanisms have impact on epigenetic therapy, MHC-I resistant HNSCC therapies, and poor CD8+ and dendritic cell infilterated tumors.

cancer biology↗