About

Maria Kukuruzinska is an Associate Dean for Research, Professor of Translational Dental Medicine, Director of the Predoctoral Research Program, and Chair of the Department of Translational Dental Medicine at Boston University Henry M. Goldman School of Dental Medicine. Her research focuses on elucidating the regulatory mechanisms underlying the interactions between the metabolic pathway of protein N-glycosylation and intercellular adhesion in tissue development and disease. Her laboratory has demonstrated the critical role of N-glycosylation in the function of E-cadherin, a major epithelial cell-cell adhesion receptor, affecting the maturity of adherens junctions and the assembly of tight junctions, as well as cytoskeletal dynamics. She investigates the molecular mechanisms through which cell-cell adhesion structures regulate N-glycosylation, with particular emphasis on the bidirectional feedback loop involving the DPAGT1 gene. Kukuruzinska's work extends to the development of salivary glands, where she studies how E-cadherin influences morphogenesis, proliferation, and ductal axis extension during submandibular gland development, with a focus on N-glycosylation's regulatory role. Her research also addresses the molecular basis of oral cancer, particularly how aberrant N-glycosylation promotes oral squamous cell carcinoma progression and how partial inhibition of N-glycosylation can stabilize intercellular adhesion and induce mesenchymal to epithelial transition. Additionally, she has initiated studies on Sjogren’s Syndrome, an autoimmune disease affecting salivary and lacrimal glands, exploring defective intercellular adhesion as a potential underlying cause. She co-founded the Norwegian-United States Initiative on Sjogren’s Syndrome (NUSSIS) to facilitate international collaboration among researchers and clinicians. Her contributions have advanced understanding of the molecular pathways involved in tissue development, cancer progression, and autoimmune disease, emphasizing the importance of N-glycosylation and cell adhesion mechanisms.

Research topics

• Cancer research
• Medicine
• Chemistry
• Bioinformatics
• Internal medicine
• Genetics
• Biology
• Pathology
• Biochemistry

Selected publications

• A highly resolved integrated single-cell atlas of HPV-negative head and neck cancer

  Communications Medicine · 2026-03-11

  articleOpen access

  Head and Neck Squamous Cell Carcinomas (HNSCC) are the seventh most prevalent form of cancer and are associated with human papilloma virus infection (HPV-positive) or with tobacco and alcohol use (HPV-negative). HPV-negative HNSCCs have a high recurrence rate, and individual patients’ responses to treatment vary greatly due to the high level of cellular heterogeneity of the tumor and its microenvironment. Here, we describe a HPV-negative HNSCC single cell atlas, which we created by integrating six publicly available datasets encompassing over 230,000 cells across 54 patients. We classify cell types, subpopulations, and their expression programs in the immune, mesenchymal, endothelial and epithelial compartments. We interrogate the relationship between cell types through hierarchical clustering, cell-cell communication analysis and correlating populations changing together across patients. We resolve the myeloid and fibroblast compartments, revealing an IL1B+ myeloid population previously unexplored in HNSCC and clarifying two immune cancer associated fibroblast populations that are frequently conflated, identify sex-associated changes in cell type proportions, and a unique interaction between CXCL8-positive fibroblasts and vascular endothelial cells. We utilize the atlas to contextualize the relationships between existing signatures and cell populations, harmonize nomenclature across studies, and show the power of this large-scale resource to robustly identify associations between transcriptional signatures and clinical phenotypes that would not be possible to discover using fewer patients. Beyond our findings, the atlas serves as a public resource for the high-resolution characterization of tumor heterogeneity of HPV-negative HNSCC. Kroehling et al. build an integrated single-cell RNA-sequencing atlas of HPV-negative head and neck squamous cell carcinoma comprising over 230,000 cells from 54 patients. It revels distinct immune, stromal, and tumor populations, harmonizes annotations and links transcriptional profiles to clinical features. HPV-negative head and neck squamous cell carcinomas (HNSCC) are a type of cancer that develops in and around the mouth and is often linked to smoking and drinking alcohol. They have a high recurrence rate and respond differently to treatment due to the high level of variation between patients in both their tumor cells and surrounding cells. In this study, we combined cell-level data from many people with HPV-negative HNSCC to create a large, unified dataset of the cell types found in these tumors. Using computational analyses, we identified and characterized the different cell types and their features. We then related those cellular features to how the tumors behaved in different patients. These results advance our understanding of how particular combinations of tumor and surrounding cells can influence cancer growth and treatment response. This knowledge could help guide more precise, personalised approaches to treating HNSCC.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-22 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Head and neck cancer with its major subsite, oral squamous cell carcinoma (OSCC), is a devastating malignancy with limited treatment options. Given that recent advances in nutritional interventions have been recognized as potential strategies for targeting cancer, we investigated the role of dietary serine restriction in OSCC cell plasticity. Utilizing multiple human OSCC-derived cell lines and an orthotopic syngeneic mouse model of OSCC, we interrogated the impact of serine deprivation on this malignancy through biochemical assays, transcriptomic analyses, and CUT&RUN sequencing, as well as impact on tumor growth and its immune environment. We report that human OSCC cells behaved like serine auxotrophs, depending on exogenous serine for growth and maintenance of plastic cell states. We show that dietary restriction of serine induced endogenous serine synthesis and generated alpha-ketoglutarate (αKG), a co-substrate for JMJD3 nuclear dioxygenase, which demethylates H3K27me3 and de-represses differentiation genes. This was accompanied by the reduction of H3K4me3 at stemness and epithelial-to-mesenchymal transition (EMT) genes caused. Likewise, dietary serine restriction inhibited orthotopic OSCC isograft growth in mice concomitant with downregulation of H3K27me3 and increased immune infiltration in the tumor periphery. Collectively, our study provides new insights into the epigenetic etiology of OSCC that reveals the interplay between serine metabolism and epigenetic molecular mechanisms driving OSCC cell plasticity and tumorigenesis. The dependence of OSCC cells on exogenous serine to maintain plastic cell states offers a unique opportunity to utilize a non-toxic dietary serine restriction as an intervention treatment either alone or in combination with other therapies for OSCC patients.

  PublisherOA PDFDOI

• Additional file 3 of Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer

  Figshare · 2025-01-01

  datasetOpen accessSenior author

  Tabular ranked gene list file (viewable in Excel) pertaining to differential gene expression testing comparing siRNA-mediated knockdown of β-catenin versus scrambled siRNA control in HSC-3 cells used for GSEA. Fields indicate gene symbol and t test statistic of differential expression, respectively, used as input to the pre-ranked GSEA tool. (TXT 289 kb)

  PublisherDOI

• Additional file 2 of Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer

  Figshare · 2025-01-01

  datasetOpen accessSenior author

  Tabular spreadsheet file containing both table of differential gene expression results comparing ICG-001 treatment (n = 3) versus DMSO (vehicle) control (n = 3) in HSC-3 and CAL27 OSCC cell lines, as well as the ICG-001 treatment gene expression signatures derived thereof (see manuscript “Methods”). (XLSX 4246 kb)

  PublisherDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-17 · 2 citations

  preprintOpen access

  Abstract 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 (IFNγ) 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 IFNγ. 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 Significance LSD1-mediated unique mechanisms have impact on epigenetic therapy, MHC-I resistant HNSCC therapies, and poor CD8+ and dendritic cell infilterated tumors.

  PublisherOA PDFDOI

• LSD1 Inhibition Induces MHC-I and Dendritic Cell Activation to Promote Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

  Cancer Research · 2025-10-09 · 2 citations

  article

  Poor infiltration of CD8+ T cells and dysregulation of MHC class I (MHC-I) confer resistance to anticancer immunotherapies. Inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been shown to increase CD8+ T-cell infiltration in head and neck squamous cell carcinoma (HNSCC). In this study, we aimed to elucidate the mechanisms of LSD1 inhibition in antitumor immunity in HNSCC to aid in the development of effective therapeutic strategies. LSD1 inhibition in syngeneic and chronic tobacco carcinogen-induced HNSCC mouse models increased the recruitment of activated dendritic cells (DC), as well as CD4+ and CD8+ T cells, and the expression of IFNγ in CD8+ T cells, CXCL9 in DCs, and CXCR3 in CD4+ T cells. Humanized HNSCC mice and patient 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 of human HNSCC cells cocultured with human peripheral blood mononuclear cells resulted in MHC-I upregulation in cancer cells. LSD1 inhibition promoted CD8+ T-cell activation via a DC-dependent mechanism and induced efficient antigen presentation in CD8+ T cells. Finally, LSD1 inhibition increased H3K4me2 at the promoters of DC-related markers (BATF3 and CXCL9), T-cell markers (CXCR3), and MHC-I (HLA-A). Overall, LSD1 inhibition in tumor cells upregulates MHC-I expression and stimulates CXCL9 secretion by DCs to enhance antigen presentation and promote CD8+ T-cell activation via the CXCL9-CXCR3 signaling axis, resulting in increased IFNγ production. This may have implications for treating poorly immunogenic and immunotherapy-resistant cancers. SIGNIFICANCE: LSD1 inhibition enhances antigen presentation and reprograms the tumor microenvironment by inducing infiltration of T cells and dendritic cells, activating antitumor immunity and providing an epigenetic therapy for head and neck cancer.

  PublisherDOI

• Data from Role for the Aryl Hydrocarbon Receptor and Diverse Ligands in Oral Squamous Cell Carcinoma Migration and Tumorigenesis

  2024-03-12

  preprintOpen access

  <div>Abstract<p>Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AhR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AhR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AhR activity in two oral squamous cell lines was modulated with AhR prototypic, environmental and bacterial AhR ligands, AhR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: (i) primary OSCC tissue expresses elevated levels of nuclear AhR as compared with normal tissue, (ii) AhR mRNA expression is upregulated in 320 primary OSCCs, (iii) AhR hyperactivation with several ligands, including environmental and bacterial ligands, significantly increases AhR activity, ALDH1 activity, and accelerates cell migration, (iv) AhR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, (v) AhR knockdown inhibits tumorsphere formation in low adherence conditions, and (vi) AhR knockdown inhibits tumor growth and increases overall survival <i>in vivo</i>. These data demonstrate that the AhR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental, and bacterial AhR ligands may exacerbate OSCC by enhancing expression of these properties.</p><p><b>Implications:</b> This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, <i>in vivo</i> and <i>in vitro</i>. <i>Mol Cancer Res; 14(8); 696–706. ©2016 AACR</i>.</p></div>

  PublisherDOI

• Abstract 4335: High-resolution characterization of age-specific cell type composition changes and signaling events in HPV-negative HNSCC tumors

  Cancer Research · 2024-03-22

  article

  Abstract This study is aimed at testing the hypothesis that increased patient age fosters conditions that are favorable for head and neck squamous cell carcinomas (HNSCC) of the oral cavity development. There is a well-documented increase in cancer incidence with age observed across diverse cancer types, where elderly patients exhibit diminished survival outcomes compared to their younger counterparts. While the convergence of aging and cancer hallmarks offers valuable insights, further work is needed to elucidate the age-specific mechanisms influencing HNSCC, beyond the shared characteristics of these biological processes. To this end, we have assembled a high-quality human single-cell RNA-sequencing HNSCC atlas profiling more than 230,000 cells across more than 50 patients with ages ranging between 18 and 89, which provides a resource to investigate age-associated changes in the disease heterogeneity. For this library, we integrated six publicly available single-cell RNAseq datasets from 54 HPV-negative patients to create the atlas. Cells were clustered, classified, characterized by gene set enrichment analysis, both in the epithelial cell compartment and in the tumor microenvironment (TME). Differential cell type proportion analysis was performed to identify cell types enriched in young (<49 years) or old (>70 years) patients. Cell-cell communication analysis was performed to identify signaling events occurring between different populations, and how these and specific ligand-receptor pairs differed in patients of different ages. CNV analyses were performed to identify cancer subclones and assess level of variation across tumors. Interestingly, we identified distinct cell populations and signaling events that associate with age, and we were able to compare, validate and recapitulate these observations in the 4MOSC1 OSCC isograft tumor model in old and young mice. Additional notable findings include a differential enrichment for cytotoxic CD8 T cells over dysfunctional CD8 T cells in young patients when compared to old, suggesting younger patients have a more effective immune TME. We also found an enrichment for cancer-associated fibroblast populations in old patients (myCAFs) that send collagen signals to malignant epithelial cells, a result we have recapitulated using the 4MOSC1 model, and hypothesize may play a role in ECM stiffening, EMT, and metastasis. Further analyses are ongoing, and we plan to validate the hypotheses generated, specifically the presence of differential abundance of specific cell populations, and age-specific ligand-receptor signaling events that lead to tumor growth. Citation Format: Lina Kroehling, Anthony Spinella, Maria Kukuruzinska, Xaralabos Varelas, Stefano Monti. High-resolution characterization of age-specific cell type composition changes and signaling events in HPV-negative HNSCC tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4335.

  PublisherDOI

• Abstract LB288: Reducing the effect of cellular stress in murine oral tumors with pharmacological blockade of β-catenin/CBP activity

  Cancer Research · 2024-04-05

  article

  Abstract Oral squamous cell carcinoma (OSCC), a primary subtype of head and neck squamous cell carcinoma (HNSCC), is a complex malignancy comprising multiple anatomical sites. OSCC ranks among the deadliest cancers globally, with a 5-year survival rate of ~65%. In previous studies, we have shown that pharmacological blockade of Wnt/β-catenin/CBP activity with small molecule inhibitors effectively abolished oncogenic cell phenotypes in OSCC. However, the underlying mechanisms promoting changes in OSCC cell identities remain unknown. To address this knowledge gap, we used an immunocompetent mouse model of OSCC induced by a tobacco-derived carcinogen, 4-nitroquinoline-1-oxide (4NQO), to interrogate cell states by single-cell RNA sequencing (scRNAseq) of tongue tissues from healthy mice (n=2), 4NQO-derived mouse tongue OSCC (n=2), and from 4NQO-derived mouse tongue tissues treated with an inhibitor of β-catenin/CBP (n=4), and generated a high-quality dataset comprising ~50K cells across all conditions. We performed multiple analyses of the generated data to catalogue the cell type repertoire and its changes among conditions. We observed significant changes in cellular composition between the 4NQO-induced and inhibitor-treated groups. The proportion of epithelial cells decreased upon treatment consistent with greatly diminished tumor volumes, while endothelial and fibroblast populations increased compared to the 4NQO control group. Epithelial sub-typing using known markers revealed a decrease in basal cancer stem-like cells (Krt5+, Krt14+) concomitant with an increase in cycling cells (Top2a+, Cdc20+). In addition, we identified a decrease in a stress cell phenotype associated with the AP-1 complex (Jun+, Fos+). The latter subgroup exhibited a positive enrichment for the “stress” module (n=100 genes) derived from human HNSCC patients described by Puram et al. To further validate the relationship between the stress subtype with β-catenin/CBP activity and its relation to the AP-1 complex, we projected the Puram stress module and the down-regulated signature from the β-catenin/CBP inhibitor-treated group compared with the 4NQO-control group onto independent cohorts of human subjects with HPV-negative HNSCC. We used both the bulk TCGA RNA-seq subset (n=367 patients) and a previously published scRNAseq dataset from Choi et al., specifically profiling the epithelial compartment (3K cells, n = 16 patients). We observed highly significant positive association of the stress program and β-catenin/CBP activity in both datasets (pearson ρ = 0.74 and 0.70, respectively), indicating that inhibition of β-catenin/CBP activity reduces the stress response. Our results suggest that mitigation of tumorigenic profiles in 4NQO-induced tumors upon inhibition of β-catenin/CBP signaling in OSCC may serve as an effective treatment strategy for the benefit of human patients and shed further light into the molecular mechanisms driving treatment response. Citation Format: Mohammed Muzamil Khan, Eric Reed, Lina Kroehling, Kenichi Nomoto, Junji Matsui, Manish Bais, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti. Reducing the effect of cellular stress in murine oral tumors with pharmacological blockade of β-catenin/CBP activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB288.

  PublisherDOI

• Abstract LB156: Targeting epigenetic activity of beta-catenin/CBP impedes oral cancer progression

  Cancer Research · 2024-04-05

  articleOpen accessSenior author

  Abstract Head and neck cancer is a complex malignancy with its major anatomical subsite, cancer of the oral cavity, ranking among the most deadly and disfiguring cancers. Oral cancer presents primarily as HPV-negative oral squamous cell carcinoma (OSCC) whose etiology is associated with tobacco and alcohol use and for which there are limited treatments. Whereas immunotherapies, such as anti-PD-1 antibodies, have become a promising therapeutic option, only ~20% of head neck cancer patients benefit from anti-PD-1 immunotherapy. We and others have shown that non-mutational epigenetic reprogramming mediated by the β-catenin/CBP complex promotes aggressive cell phenotypes in OSCC by establishing open chromatin at the transcription start sites of genes associated with cancer stemness. Accordingly, pharmacological inhibition of this complex dramatically inhibits OSCC evolution in a syngeneic mouse model of OSCC. Here, we evaluated whether the inhibition of β-catenin/CBP epigenetic activity would enhance the effects of anti-PD-1 immunotherapy. We adapted a syngeneic mouse model of tobacco-associated oral carcinogenesis that utilizes a mouse cell line, 4MOSC1, derived from 4-nitroquinoline-1 oxide- (4NQO)-induced tongue tumors of C57BL/6J mice. After tumors developed for 7 days, mice were blindly separated into treatment cohorts (n=13, each) to receive vehicle control (PBS), monotherapy (either 10 mg/kg anti-PD-1 EOD IP, or 100 mg/kg E7386, a Wnt signaling pathway modulator, QD oral gavage) or combination therapy (anti-PD-1 + E7386). Tumor isografts were harvested 11 days post initiation of treatments and processed for histopathology, immunohistochemistry, and immunofluorescence analyses. Measurements of tumor volumes showed that combination therapy resulted in a statistically significant reduction by ~80% compared to control mice and that it surpassed tumor decrease by either monotherapy. These results were confirmed by histopathology analyses. Evaluation of tumor tissues by immunofluorescence revealed statistically significant decreases in Cbp, H3K4me3, Keratin 14, and Podoplanin expression in response to E7386 alone and in combination with anti PD-1. Collectively our results suggest that a combination therapy comprising anti PD-1 treatment with E7386-targeting β-catenin/CBP epigenetic signaling is likely to impede OSCC evolution to advanced disease. Supported by Eisai, Co Ltd Research Award (MAK), NIH 5R01 DE030350 (MAK, SM, XV) and 5R01 DE031413 (MVB). Citation Format: Emily Fisher, Anthony Spinella, Junji Matsui, Kenichi Nomoto, Xaralabos Varelas, Manish Bais, Maria Kukuruzinska. Targeting epigenetic activity of beta-catenin/CBP impedes oral cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB156.

  PublisherDOI

Recent grants

• Regulation of SMG Development by Adhesion Receptors

  NIH · $2.6M · 2002–2014

• NIH Grant K04DE000362

  NIH · $338k · 1999

• NIH Grant R01DE010183

  NIH · $3.3M · 2009

• Repair, Regeneration and Fibrosis of the Salivary Gland

  NIH · $456k · 2015–2018

• NIH Grant R01DE015304

  NIH · $1.5M · 2012

Frequent coauthors

• Saul Roseman

  104 shared

• Nancy L. Weigel

  86 shared

• E. Bruce Waygood

  University of Saskatchewan

  86 shared

• Kelley Lennon

  John Hunter Hospital

  59 shared

• Stefano Monti

  53 shared

• Atsushi Nakazawa

  49 shared

• Xaralabos Varelas

  Boston University

  44 shared

• Manish V. Bais

  Boston University

  43 shared

Labs

• Office for ResearchPI

Education

• Ph.D.

  Johns Hopkins University

  1983

• Other, Post-doctoral training

  Massachusetts Institute of Technology

  1984