Biology subjects

El-Naggar, A. K.

Publications and source records attributed to El-Naggar, A. K..

3 recordsLinked to original sources

bioRxiv2026

Multi-omics analysis identifies intrinsic Trp53 driven metastatic breast cancer subtypes.

Metastatic breast cancer (mBC) is deadly, and its molecular drivers are largely unknown. Treatment is limited to systemic cytotoxic chemotherapies and tumors often become refractory. The most frequently mutated gene in MBC is TP53. The TP53R248W hotspot missense mutation is associated with poor prognosis. We generated a somatic mouse model of mammary epithelial specific Trp53R245Wexpression. Primary tumors were highly metastatic, reflecting the human molecular subtypes luminal A, luminal B, HER2, and TNBC. Transcriptomic profiling revealed three intrinsic subtypes: stem-cell like (SCL), well-differentiated metabolically active (WDMA), and immunosuppressed (IS). SCL tumors activate ribosome biosynthesis and E2F signaling, amplifying Met, Birc3, Yap1 and deleting Nf1, Pik3r1, and Rad17. WDMA tumors activate cytochrome P450 enzymes, estrogen signaling and branched chain amino acid degradation, with mutations activating Pi3k/Akt/mTOR signaling. IS tumors activate immune suppression, have high mutation burden, and frequently mutate Traf7 and delete Cdkn2a. This is the most comprehensive transcriptomic and genomic profiling of mutant p53-driven breast tumors, elucidating potential therapeutic targets. TeaserA single Trp53 mutation drives intrinsic metastatic breast cancer subtypes with distinct transcriptomes and genomic alterations.

cancer biology↗

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↗

bioRxiv2021

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes, but the impacts of integration in tumorigenesis remain unclear. Analysis of 105 HPV-positive oropharyngeal cancers by whole genome sequencing detects viral integration in 77%, revealing five statistically significant integration hotspots near genes that regulate epithelial stem cell maintenance (i.e. SOX2, TP63, FGFR, MYC) and immune evasion (i.e. CD274). Somatic hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with local density of HPV integrants. Genes expressed at extreme outlier levels are increased 86-fold within +/- 150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking and/or de novo expression of noncoding or imprinted genes. We conclude that HPV integration contributes substantively to cancer development by causing extensive disruption of host genome structure and gene expression.

genomics↗