Biology subjects

Yadollahi, P.

Publications and source records attributed to Yadollahi, P..

5 recordsLinked to original sources

bioRxiv2025

NOTCH1 Acts as a Tumor Suppressor That Induces Early Differentiation in Head and Neck Cancer

We identified frequent inactivating notch1 mutations in HNSCC over a decade ago, indicating its role as a tumor suppressor--unlike its oncogenic function in leukemias and salivary gland tumors. However, there has been much debate in the literature regarding a possible oncogenic role in HNSCC as well, based on reports that notch1 signaling drives tumor growth and a cancer stem cell phenotype in some HNSCC tumor lines and patient samples. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to the prognosis and personalized therapy of patients with either wild-type or mutated NOTCH1. Here we present a systematic and comprehensive investigation unequivocally demonstrating that notch1 signaling functions as a tumor suppressor in HNSCC regardless of mutation or activation status and leads to reduction in frequency of cancer stem cells. We develop a robust gene expression signature of notch1 activation based on experimental data that when applied to patient samples shows notch1 signaling is associated with very early differentiation, an altered tumor microenvironment, and better prognosis-- consistent with a tumor suppressive role. Our work unifies the field by reconciling conflicting data and providing critical insights into the biological and clinical significance of the NOTCH1 pathway in HNSCC.

cancer biology↗

bioRxiv2025

Novel transcription factor BTNL9 enhances tumor suppression and drug sensitivity in non-small cell lung cancer through cell cycle regulation

BackgroundButyrophilins (BTNs) are immunoglobulin superfamily proteins involved in immune regulation. Among them, BTNL9 has unique structural features, including a bZIP-like domain, suggesting a potential transcriptional role. While BTNL9 is known to suppress T cell activation, its function in cancer remains largely unexplored. Recent studies suggest it may inhibit tumor progression and correlate with improved prognosis in multiple cancers. However, its molecular mechanisms and regulatory impact on lung cancer remain unclear. This study investigates the role of BTNL9 as a transcription factor and its implications for tumor progression and therapy. MethodsChIP-seq identified BTNL9-binding sites, followed by RNA-seq to assess transcriptomic profiles and validated by western blot. Drug sensitivity was evaluated through cytotoxicity assays. A xenograft model was applied to assess the effect of BTNL9 on tumor growth. TCGA data analysis examined correlations with survival, cell cycle regulators, and immune infiltration. ResultsChIP-seq identified 26,610 BTNL9 binding peaks, mapping to 9,707 genes near transcription start sites. RNA-seq and western blotting showed BTNL9 regulates cell cycle (E2F1, CDKN1A, CDK1, CDC25C, FOXM1), DNA replication (MCM2/3/7, ORC6), and p53-related transcription (BBC3, GADD45A). Integrative analysis found that 74.8% of differentially expressed genes were directly regulated by BTNL9. Functionally, BTNL9 overexpression induced cell cycle arrest, reduced proliferation, and suppressed tumor growth in vivo. BTNL9 enhanced bortezomib sensitivity in both A549 and NCI-H460 cells, with etoposide effects being more pronounced in A549. Higher BTNL9 levels strongly suppressed the expression of FOXM1, CDC25C, CDK1, CDK2, CCNA2 and CCNB1 and negatively correlated with these markers in LUAD TCGA data. Elevated BTNL9 expression was associated with improved survival, complete remission, and increased immune infiltration, including macrophages, CD8+ T cells, NK cells, and B cells in cancer tissues. ConclusionsBTNL9 functions as a transcription factor, suppresses tumor growth, and enhances drug sensitivity. Its correlation with survival and immune infiltration suggests potential role as a tumor suppressor and predictive biomarker for chemotherapy response.

cancer biology↗

bioRxiv2025

Bypassing cisplatin resistance in Nrf2 hyperactivated head and neck cancer through effective PI3Kinase targeting

BackgroundFor patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g., NOTCH1 mutations). PurposeWe evaluated the efficacy of PI3K inhibitors (PI3Ki) in bypassing Nrf2-mediated cisplatin resistance in HNSCC. MethodsWe measured transcriptomic, metabolomic and signaling changes driven by PI3Kis in cisplatin-resistant HNSCCs in vitro and tested efficacy in vivo in subcutaneous, orthotopic and metastatic xenograft models using immunodeficient and humanized murine models of HNSCC coupled with spatial transcriptomics. ResultsThe PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade as demonstrated in an in vivo shRNA screen. The PI3Ki gedatolisib inhibits cisplatin-resistant HNSCC proliferation, induces G2M arrest and potentiates cisplatin effectiveness through activation of autophagy, senescence and disruption of fatty acid metabolism. Gedatolisib suppresses HNSCC tumor growth in orthotopic and metastatic settings and demonstrates profound anti-tumor activity in humanized murine models of HNSCC, coupled with a reduction in hypoxia-rich regions and reduced infiltration by regulatory T lymphocytes. ConclusionOur findings emphasize the critical role of the PI3K-AKT-mTOR pathway in cisplatin-resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors. Gedatolisib induced metabolic regulation and substantial re-sensitization of resistant cells to cisplatin, positioning it as a promising candidate for combination therapies aimed at overcoming primary chemo-radiation failure in HNSCC. Statement of translational relevanceCisplatin resistance, whether intrinsic or acquired, translates to treatment failure and nearly universal death in head and neck squamous cell carcinoma (HNSCC). However, the development of effective systemic regimens for cisplatin-resistant HNSCC has not yet been successful. Here, we present, for the first time, a mechanistic, biomarker-informed strategy for effective targeting of the PI3Kinase pathway in cisplatin-resistant HNSCC with substantial anti-tumor activity in both orthotopic and metastatic models, which may be capable of bypassing or reversing cisplatin resistance in this disease.

cancer biology↗

bioRxiv2024

Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer

PurposeExposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data link cigarette smoke as a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming the cellular reductive state. Experimental designUsing established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to analyze the impact of smoke exposure on HNSCC tumor biology. ResultsCigarette smoke persistently activated Nrf2 target genes essential for maintenance of the cellular reductive state and survival under conditions of increased oxidative stress in HNSCC regardless of HPV status. In contrast to e-cigarette vapor, conventional cigarette smoke mobilizes cellular metabolism toward oxidative stress adaptation, resulting in development of cross-resistance to cisplatin. In parallel, smoke exposure modulates both expression of PDL1 and the secretory phenotype of HNSCC cells through activation of NF-{kappa}B resulting in an altered tumor immune microenvironment (TIME) in syngeneic mouse models and altered PBMC differentiation that includes downregulated expression of antigen presentation and costimulatory genes in myeloid cells. ConclusionCigarette smoke exposome is a potent activator of the Nrf2 pathway and is a likely primary trigger for the tripartite phenotype of aggressive HNSCC consisting of: 1) reduced chemotherapy sensitivity, 2) enhanced metastatic potential and 3) suppressed anti-tumor immunity. Statement of significanceThe smoke exposome drives aggressive tumor behavior, treatment resistance and suppressed immunity through coordinated metabolic reprogramming. Successfully targeting this adaptation is critical to improving survival in smokers with head and neck cancer.

cancer biology↗

bioRxiv2024

Reliable RNA-seq analysis from FFPE specimens as a means to accelerate cancer-related health disparities research

Whole transcriptome sequencing (WTS/ RNA-Seq) is a ubiquitous tool for investigating cancer biology. RNA isolated from frozen sources limits possible studies for analysis of associations with phenotypes or clinical variables requiring long-term follow-up. Although good correlations are reported in RNA-Seq data from paired frozen and formalin fixed paraffin embedded (FFPE) samples, uncertainties regarding RNA quality, methods of extraction, and data reliability are hurdles to utilization of archival samples. We compared three different platforms for performing RNA-seq using archival FFPE oropharyngeal squamous carcinoma (OPSCC) specimens stored up to 20 years, as part of an investigation of transcriptional profiles related to health disparities. We developed guidelines to purify DNA and RNA from FFPE tissue and perform downstream RNA-seq and DNA SNP arrays. RNA was extracted from 150 specimens, with an average yield of 401.8 ng/cm2 of tissue. Most samples yielded sufficient RNA reads >13,000 protein coding genes which could be used to differentiate HPV-associated from HPV-independent OPSCCs. Co-isolated DNA was used to identify patient ancestry. Utilizing the methods described in this study provides a robust, reliable, and standardized means of DNA & RNA extraction from FFPE as well as a means by which to assure the quality of the data generated.

cancer biology↗