Biology subjects

Navab, R.

Publications and source records attributed to Navab, R..

3 recordsLinked to original sources

bioRxiv2026

Tumor Microenvironment Modulates Lineage Plasticity in Lung Squamous Cell Carcinoma

Lung squamous cell carcinoma (LUSC) is the second most common type of lung cancer, yet therapeutic options remain limited. A deeper understanding of its biology and molecular pathogenesis is essential for developing new treatment strategies. Here, we investigated the mechanisms of phenotypic plasticity in LUSC by comparing organoid-derived orthotopic lung models (ODOLs) and subcutaneous xenograft models (ODXs). ODXs showed greater tumor growth, squamous differentiation, and extracellular matrix (ECM) organization compared to ODOLs. Transcriptomic analyses revealed upregulation of multiple HIF1 and SOX2 target genes together with enhanced hypoxia signaling in ODXs. CRISPR/Cas9-mediated HIF1-knockout ODXs showed reduced SOX2 expression, tumor growth, and ECM organization, whereas SOX2-knockout ODXs reduced tumor growth without affecting HIF1 and ECM organization. These results indicate that HIF1 regulates squamous lineage maintenance through SOX2 and ECM remodeling. Spatial transcriptomics revealed enrichment of basal cell-like and squamous-differentiated tumor states in ODXs, whereas ODOLs displayed less differentiated phenotypes. These findings identify the tumor microenvironment as a critical determinant of lineage plasticity in LUSC and provide mechanistic insight into how hypoxia shapes tumor differentiation.

Cancer Biology↗

bioRxiv2022

Unsupervised determination of lung tumor margin with widefield polarimetric second-harmonic generation microscopy

The extracellular matrix (ECM) is amongst many tissue components affected by cancer, however, morphological changes of the ECM are not well-understood and thus, often omitted from diagnostic considerations. Polarimetric second-harmonic generation (P-SHG) microscopy allows for visualization and characterization of collagen ultrastructure in the ECM, aiding in better understanding of the changes induced by cancer throughout the tissue. In this paper, a large region of hematoxylin and eosin-stained human lung section, encompassing a tumor margin, connecting a significant tumor portion to normal tissue was imaged with P-SHG microscopy. The resulting polarimetric parameters were utilized in principal components analysis and unsupervised k-means clustering to separate normal- and tumor-like tissue. Consequently, a pseudo-color map of the clustered tissue regions is generated to highlight the irregularity of the ECM collagen structure throughout the region of interest and to identify the tumor margin.

pathology↗

bioRxiv2018

Non-driver somatic alteration burden confers good prognosis in non-small cell lung cancer

BackgroundGenomic profiling of patient tumors has linked somatic driver mutations to survival outcomes of non-small cell lung cancer (NSCLC) patients, especially for those receiving targeted therapies. However, it remains unclear whether specific non-driver mutations have any prognostic utility.\n\nMethodsWhole exomes and transcriptomes were measured from NSCLC xenograft models of patients with diverse clinical outcomes. Penalised regression analysis was performed to identify a set of 865 genes associated with patient survival. The number of somatic copy number aberrations, point mutations and associated expression changes within the 865 genes were used to stratify independent NSCLC patient populations, filtered for chemotherapy naive and early-stage. In-depth genomic analysis and functional testing was conducted on the genomic alterations to understand their effect on improving survival.\n\nResultsHigh burden of somatic alterations are associated with longer disease-free survival (HR=0.153, P=1.48x10-4) in NSCLC patients. When somatic alterations burden was integrated with gene expression, we were able to predict prognosis in three independent patient datasets. Patients with high alteration burden could be further stratified based on the presence of immunogenic mutations, revealing another subgroup of patients with even better prognosis (85% with >5 years survival), and associated with cytotoxic T-cell expression. In addition, 95% of these 865 genes lack documented activity relevant to cancer, but are in pathways regulating cell proliferation, motility and immune response were implicated.\n\nConclusionOur results demonstrate that non-driver somatic alterations may influence the outcome of cancer patients by increasing beneficial immune response and inhibiting processes associated to tumorigenesis.

cancer biology↗