About

Dr. Raquel Sitcheran received her Bachelor of Arts in biology from Columbia University in 1992 and her PhD in physiology and genetics from the University of California, San Francisco in 2000, working with Dr. Keith Yamamoto. Her postdoctoral work was conducted with Dr. Albert Baldwin at the University of North Carolina, Chapel Hill. She served as a research associate at the Lineberger Comprehensive Cancer Center at UNC Chapel Hill from 2006 to 2009 before joining the faculty at the Texas A&M University Naresh K. Vashisht College of Medicine in September 2009. Her research focuses on the role of NF-κB regulatory proteins in regulating cancer cell behavior, particularly their motility and invasive potential. She studies how signals regulate NF-κB and how deregulation of this pathway impacts cancer cell growth, self-renewal, and survival. Her laboratory has established a critical role for NIK and noncanonical NF-κB signaling in promoting the migratory and invasive potential of glioma cells. Current efforts include elucidating mediators of NIK signaling in mitochondria within cancer and normal cells to understand how mitochondrial dysfunction contributes to disease and cancer progression.

Research topics

• Biology
• Genetics
• Cancer research
• Cell biology
• Immunology
• Neuroscience
• Chemistry
• Biochemistry

Selected publications

• Abstract B050: Mitochondrial NF-kB–inducing kinase orchestrates metabolic fitness, stress responses and immune signaling in glioma

  Cancer Research · 2026-03-23

  articleSenior author

  Abstract Background: While NF-kB-inducing-kinase (NIK, MAP3K14) is primarily recognized for its key functions in immunity and inflammation, recent studies suggest a critical role for NIK as a bioenergetic rheostat that links mitochondrial stress and metabolic adaptation in glioma progression. We previously demonstrated that a discrete pool of NIK localizes to mitochondria in glioma cells where it promotes oxidative metabolism, metabolic fitness, cell survival, invasion and proliferation. Indeed, NIK knockout (NIKKO) glioma cells exhibit substantially reduced oxygen consumption and impaired overall metabolic capacity with a compensatory shift toward glycolysis, indicating that glioma cells co-opt mitochondrial NIK to support tumor progression. Notably, these metabolic functions are independent of downstream NF-kB signaling and the mechanism by which NIK rewires cancer cell metabolism remains unknown, thereby limiting the ability to therapeutically exploit this pathway. Methods: Whole-cell proteomic analysis was used to define metabolic dysfunction in NIKKO glioma cells. Immunoprecipitation–mass spectrometry and proximity ligation assays with confocal microscopy were performed to identify mitochondrial NIK-interacting proteins. Site-directed mutagenesis and structure–function analyses were used to map and characterize putative NIK GxxxG and WN motifs, conserved sequences shown to mediate mitochondrial inner membrane protein-protein interactions. The effect of NIK mutations (GxxxG to LxxxL and WN to AA) on mitochondrial function and NF-kB signaling were evaluated using metabolic, biochemical, and immunoblot assays. Results: The top dysregulated pathways in NIKKO glioma cells include impaired mitochondrial respiration, stress response and quality control, as well as heightened innate/adaptive immune signaling and antigen presentation. NIK was observed to interact with several mitochondrial proteins, including TIM50 and TIM8A. Mutating conserved GxxxG and WN motifs identified in NIK abrogated mitochondrial respiration and metabolic fitness in glioma cells. Immunoblot analysis revealed no impairment of activation of either the canonical or non-canonical NF-κB pathway in NIK-mutants compared to wild-type NIK cells, suggesting a novel independent role for NIK at mitochondria. Conclusions: Our findings identify NIK as a putative mitochondrial scaffold, revealing a previously unrecognized function for NIK in integrating bioenergetic state, stress signaling programs and innate immune antigen-presentation pathways in glioma. These data position mitochondrial NIK as a tractable therapeutic target to reprogram glioma cell metabolism and enhance potential responsiveness to immunotherapy. Moreover, by directly linking mitochondrial function in tumor cells to immune activation pathways, mitochondrial NIK emerges as a key regulator of the neuro-immune landscape that shapes glioma progression and treatment response. Citation Format: Victoria Bunting, Raquel Sitcheran. Mitochondrial NF-kB–inducing kinase orchestrates metabolic fitness, stress responses and immune signaling in glioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B050.

  PublisherDOI

• Abstract B052: NF-κB-Inducing Kinase (NIK) in microglia promotes male-specific glioblastoma tumor pathogenesis

  Cancer Research · 2026-03-23

  articleSenior author

  Abstract Introduction: Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor, characterized by profound therapy resistance and striking sex disparities, where males experience higher incidence and poorer survival than females. The GBM tumor microenvironment (TME) is highly immunosuppressive and dominated by microglia and infiltrated myeloid cells that promote tumor growth, invasion, and immune evasion. Our previous studies have established NF-κB–Inducing Kinase (NIK) as a central regulator of cancer cell metabolic reprogramming and macrophage immune-metabolic activation. However, how NIK influences the metabolic and signaling landscape of the brain immune TME, and whether these effects differ between sexes, remains unclear. Methods: We employed systemic and cell type-specific conditional knockout mouse models to identify the role of NIK in the GBM TME. Orthotopic implantation of syngeneic GL261 tumors was followed by survival, transcriptomic and immunohistochemical analyses to define how NIK loss impacts tumor growth, immune composition, and molecular signaling pathways. Results: Both systemic and microglia-specific NIK deletion markedly reduced GBM tumor size and progression. Interestingly, microglial NIK ablation significantly improved survival in male but not female hosts, indicating sex-dependent differences in NIK tumor-promoting functions. In contrast, astrocyte- and myeloid-specific NIK deletion failed to reproduce these effects, confirming a unique microglial-intrinsic mechanism. Transcriptomic analyses demonstrated that loss of microglial NIK altered extracellular matrix remodeling, cell migration, angiogenesis, and cytokine signaling - key processes related to GBM progression. Conclusion: Collectively, our findings highlight microglial NIK as a pivotal modulator of GBM progression that integrates immune-metabolic and tissue remodeling in a sex-dependent manner. Targeting NIK within microglia may suppress tumor growth and improve survival outcomes, particularly in males, underscoring the necessity of integrating sex as a biological variable in GBM research. Significance: This study uncovers a previously unrecognized microglial NIK-dependent signaling axis that drives brain tumor progression. These new insights advance our understanding of neuroimmune-tumor crosstalk and positions NIK as a promising therapeutic target for precision, cell type- and sex-informed GBM therapy. Citation Format: Hasara N. Abeygunaratne, Justin N. Keeney, Raquel Sitcheran. NF-κB-Inducing Kinase (NIK) in microglia promotes male-specific glioblastoma tumor pathogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B052.

  PublisherDOI

• Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease

  Nature Communications · 2025-05-20 · 7 citations

  articleOpen access

  Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD. Mitochondrial diseases lead to chronic health impairment, aggravated by infections and other environmental exposures. Here authors show, in a mouse model of polymerase gamma (Polg)-related mitochondrial disease, that Pseudomonas aeruginosa infection prompts innate immune hyperreactivity via interferon-mediated upregulation of caspase11 and guanylate-binding proteins, leading to lung inflammation.

  PublisherOA PDFDOI

• Tumor promoting functions of NIK/MAP3K14 in the Glioblastoma Microenvironment: Implications for Sex-Differences in Therapeutic Responses

  Endocrinology · 2025-04-01

  articleOpen access

  Abstract Text Glioblastoma multiforme (GBM) is the most common and deadliest primary malignant brain tumor in adults due to its aggressive, invasive growth and therapy resistance. The GBM tumor microenvironment (TME) is highly infiltrated by tumor associated macrophages and microglia (TAMMs) that undergo metabolic reprogramming and acquire immunosuppressive, tumor-supporting properties. However, the mechanisms underlying this metabolic reprogramming remain poorly understood. This study aims to elucidate the role of NF-κB-Inducing Kinase (NIK), a key inducer of NF-κB signaling, in regulating TAMM metabolism, polarization, and inflammatory status in GBM. We have recently observed that NF-κB-inducing kinase (NIK, encoded by MAP3K14), a key upstream regulator of NF-κB signaling, has tumor cell-intrinsic roles in promoting GBM invasion and pathogenesis through both NF-κB-dependent and NF-κB-independent mechanisms. Our findings indicate that the NF-κB-independent tumor promoting activities of NIK include the regulation of diverse mitochondrial functions, such as mitochondrial dynamics, trafficking, oxidative metabolism and metabolic adaptation to bioenergetic stress. Similar to NIK-deficient cancer cells, microglia and macrophages lacking NIK exhibit markedly impaired OXPHOS, as well as a hyper-inflammatory phenotype. To investigate roles for NIK in the metabolic rewiring and immunosuppressive properties of the tumor stroma, we employed orthotopic, syngeneic GBM mouse models. We observed diminished tumor growth and improved survival in total NIK knockout (NIKKO) and microglia-specific NIK knockout (NIKMG-cKO) mice, revealing a critical tumor-promoting role for NIK in the GBM TME. Interestingly, this survival benefit was more pronounced in male NIKKO and NIKMG-cKO mice compared with females. We are using immunohistochemistry, multi-parameter flow cytometry, RNA-seq and metabolomics analyses to investigate alterations in TAMM infiltration, neuroinflammation, and oncogenic rewiring of lipid metabolism in NIKMG-cKO tumors. Taken together our findings highlight previously unknown functions for NIK in coordinating microglia/macrophage cell metabolism and immune cell infiltration in the GBM TME and provide new insights into developing novel, sex dependent targeted therapies. Date of Presentation October 16, 2024

  PublisherOA PDFDOI

• Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-14 · 5 citations

  preprintOpen access

  Abstract Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. Infections in MtD patients more frequently progress to sepsis, pneumonia, and other detrimental inflammatory endpoints. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear, constituting a key gap in knowledge that complicates treatment and increases mortality in this vulnerable population. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBPs) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work sheds new light on innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.

  PublisherOA PDFDOI

• Glucose-6-phosphatase is required for organelle reorganization, energy metabolism and motility of <i>Drosophila</i> sperm

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-02 · 1 citations

  preprintOpen access

  SUMMARY Glucose-6-Phosphatase (G6Pase), a key enzyme in gluconeogenesis and glycogenolysis in the mammalian liver and kidney, converts glucose-6-phosphate to glucose for maintaining systemic blood glucose homeostasis during nutrient deprivation. However, its function has remained elusive in insects, which have no need for G6Pase in sugar homeostasis since they convert glucose-6-phosphate to trehalose, their main circulating sugar, via trehalose phosphate synthase (TPS1). In this study we identify an unexpected and essential requirement for G6Pase in Drosophila male fertility, specifically to produce motile sperm. In G6P mutant males, spermatogenesis and spermiogenesis appear to proceed normally, leading to the production and transfer of mature sperm. However, once inside the female reproductive tract, G6P mutant sperm exhibit severely reduced tail beat frequency and only rarely enter an egg. Moreover, when compared to wild type sperm, G6P -deficient sperm are depleted more rapidly from the spermatheca and seminal receptacle, the female sperm storage organs. Immunohistochemical analyses show that G6P mutant spermatocytes present with an enlarged and stressed endoplasmic reticulum (ER) and a diminished Golgi apparatus. Additionally, the acrosome, a Golgi derived organelle that is critical for sperm capacitation, exhibits diminished expression of the transmembrane protein SNEAKY, which is essential to breakdown the sperm plasma membrane after fertilization. Metabolic analyses show impairment of both basal and compensatory glycolysis, as well as ATP production, in testes of G6P mutant males. Taken together, our investigations unveil a novel and crucial function for G6Pase in male fertility, highlighting its importance in regulating energy homeostasis in reproductive tissues.

  PublisherOA PDFDOI

• Author Reply to Peer Reviews of Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice

  2024-05-09

  peer-review
  PublisherDOI

• Atomic vacancies of molybdenum disulfide nanoparticles stimulate mitochondrial biogenesis

  Nature Communications · 2024-09-17 · 19 citations

  articleOpen access

  Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function. In this study, we designed molybdenum disulfide (MoS2) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS2 nanosheets. Treatment of mammalian cells with MoS2 nanoflowers increased mitochondrial biogenesis by induction of PGC-1α and TFAM, which resulted in increased mitochondrial DNA copy number, enhanced expression of nuclear and mitochondrial-DNA encoded genes, and increased levels of mitochondrial respiratory chain proteins. Consistent with increased mitochondrial biogenesis, treatment with MoS2 nanoflowers enhanced mitochondrial respiratory capacity and adenosine triphosphate production in multiple mammalian cell types. Taken together, this study reveals that predefined atomic vacancies in MoS2 nanoflowers stimulate mitochondrial function by upregulating the expression of genes required for mitochondrial biogenesis. Mitochondrial dysfunction is linked to various rare genetic disorders and common age-related diseases, but few compounds can stimulate mitochondrial activity. Here, the authors address this issue by developing atomic vacancy-rich molybdenum disulfide nanoparticles that can catalyze intracellular reactive oxygen species to enhance mitochondrial biogenesis and cellular respiration.

  PublisherOA PDFDOI

• Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice

  Life Science Alliance · 2024-07-23 · 4 citations

  articleOpen access

  Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low-folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

  PublisherOA PDFDOI

• Abstract B049: Uncovering sex-biased immunometabolic roles for NIK in the GBM tumor microenvironment

  Cancer Research · 2024-03-04

  articleSenior author

  Abstract The interconnected relationship between the central nervous system (CNS) and the immune system is crucial for brain function. Astrocytes, microglia and infiltrating macrophages perform diverse functions for the maintenance of CNS homeostasis, including inflammatory responses to injury or infection, tissue repair and immune surveillance of cancers such as glioblastoma (GBM). Indeed, these cells comprise up to 50% of GBM tumor mass, yet the impact of their interactions in regulating neuroinflammation and immunosuppression in the GBM tumor microenvironment is not well understood. We have recently found that NF-κB-Inducing Kinase (NIK), an essential activator of the noncanonical NF-κB pathway, governs the mitochondrial metabolic reprogramming that is required for the acquisition of pro-repair bone-marrow-derived macrophage (BMDM) immune effector functions. Although NIK is highly expressed in brain immune cells, including resident macrophages/microglia and astrocytes, little is known regarding NIK-dependent regulatory pathways controlling their immune cell effector functions in brain health and systemic responses to disease. Our preliminary data demonstrate that similar to BMDMs, NIK knockout (KO) microglia and astrocytes have impaired mitochondrial oxidative metabolism and skew towards pro-inflammatory phenotypes. Moreover, NIK KO mice harboring orthotopic syngeneic brain tumors exhibit improved survival and reduced microglia and macrophage tumor infiltration, suggesting that NIK functions in the TME to support immune cell interactions that promote GBM growth. Notably these effects were sex-biased, with male NIK KO mice having a more pronounced survival benefit. Additionally, we observe whole-body metabolic dysfunction in myeloid- and astrocyte-specific conditional NIK knockout mice, implying a potential NIK-dependent feedback relationship between CNS immune/glial cell functions and control of systemic metabolism. Overall, these results are consistent with poorer survival of patients with elevated NIK expression and provides a possible rationale for the higher incidence of GBM in males. Coupled with our previous work demonstrating that NIK has several GBM cell-intrinsic roles to promote tumor invasion and adaptive growth through control of mitochondrial fission and cellular metabolism, these new findings highlight the importance of understanding NIK-dependent immunometabolic functions in the brain. Therapeutic strategies targeting NIK may not only attenuate GBM cell invasion and render them vulnerable to metabolic stress, but also modulate metabolic rewiring of immune cells in the tumor microenvironment to improve patient outcomes. Citation Format: Justin N. Keeney, Caren Stuebe, Kathryn M. Pflug, L. Gerard Toussaint, Raquel Sitcheran. Uncovering sex-biased immunometabolic roles for NIK in the GBM tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B049.

  PublisherDOI

Recent grants

• Investigating Novel Functions for NIK/MAP3K14 in High-Grade Glioma

  NIH · $2.5M · 2014–2024

• NF-kappaB N-myc in Oncogenic Pathways of the CNS

  NIH · $780k · 2006–2012

Frequent coauthors

• Kathryn M. Pflug

  Bryan College

  35 shared

• Dong W. Lee

  Texas A&M Health Science Center

  27 shared

• Albert S. Baldwin

  26 shared

• Justin Keeney

  Texas A&M University

  18 shared

• Jonathan S. Serody

  15 shared

• Matthew J. O’Shaughnessy

  Memorial Sloan Kettering Cancer Center

  15 shared

• Bruce R. Blazar

  University of Minnesota

  15 shared

• Patricia C. Cogswell

  Chordoma Foundation

  10 shared