Biology subjects

Harari, P. M.

Publications and source records attributed to Harari, P. M..

3 recordsLinked to original sources

bioRxiv2026

A Novel Syngeneic Mouse Model to Study Immune Evasion in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and patient outcomes have remained largely unchanged despite advances in multimodal therapy. Immune checkpoint inhibitors (ICIs), which block the PD-1/PD-L1 axis to restore T cell-mediated anti-tumor immunity, have emerged as a promising treatment strategy. However, response rates remain below 20% in HNSCC, underscoring the need to better understand mechanisms of immune evasion within the tumor microenvironment. Syngeneic mouse models are essential for studying tumor-immune interactions, yet currently available HNSCC models are limited. Here, we report the development of a novel FVB/NJ-derived syngeneic HNSCC model generated from 7,12-dimethylbenz(a)anthracene (DMBA)-induced primary on floor of mouth/buccal tumors, designated FMOC1, FMOC2, and FMOC3 (FVB/NJ Mouse Oral Cancer). In vitro, all FMOC cell lines exhibited robust proliferative capacity with distinct proliferation kinetics. In vivo, all FMOC cell lines exhibited characteristic HNSCC histopathology, including cytokeratin 5 positivity, and were tumorigenic in immunodeficient NCG mice; however, in syngeneic immunocompetent mice, only FMOC1 demonstrated sustained tumor growth at orthotopic and flank sites, whereas FMOC2 and FMOC3 tumors underwent spontaneous regression within 2 weeks, indicating differential immune-dependent tumorigenicity among the lines. Consistent with this, depletion of CD4+ and/or CD8+ T cells restored tumor growth in FMOC2 and FMOC3 models, indicating a critical role for T cell-mediated immunity in tumor suppression. Notably, FMOC1 tumors were responsive to anti-PD-L1 and anti-CTLA-4 therapy, supporting their utility for evaluating immunotherapeutic strategies. Collectively, these findings establish the FMOC model as a novel and versatile platform to study tumor-immune interactions and immune evasion mechanisms in HNSCC, with potential applications in preclinical immunotherapy development.

cancer biology↗

bioRxiv2026

A Head and Neck Cancer Patient-Specific Microphysiological System for Predicting Response to Chemoradiation

Head and neck cancer (HNC) is the 6th most common malignancy worldwide. 60% of patients present with advanced disease and approximately 50% of patients recur following primary treatment. Chemoradiation remains a standard of care for most patients. However, clinicians lack functional tools to predict which patients will respond to chemoradiation prior to treatment and current models, including organoids and animal model systems, fail to capture either full complexity or patient-to-patient heterogeneity of the individual HNC tumor and microenvironment (TME). Here, we have developed, characterized, and tested a patient-specific microphysiological system (MPS) that reconstructs the HNC TME in a vascularized 3D environment. This MPS was constructed from malignant cells, fibroblasts, and immune cells from a patients surgically resected tumor, seeded within a 3D hydrogel with molded endothelial lumens. Single-cell RNA sequencing confirmed that the MPS preserved 12 transcriptionally distinct cell populations found in matched native tissue. The platform recapitulated tumor hypoxia, with a 12-fold increase in hypoxic marker expression that altered radiation response, consistent with clinical HNC biology. Compartment-resolved imaging revealed distinct treatment dynamics in tumor, stromal, and vascular regions, and individual patients exhibited divergent responses to chemoradiation in spheroid morphology, cell viability, and migration. We found the slope of spheroid area change with treatment tracked with tumor recurrence, suggesting this metric could serve as a functional predictor of therapeutic response.

bioengineering↗

bioRxiv2024

Chromosomal instability increases radiation sensitivity

Continuous chromosome missegregation over successive mitotic divisions, known as chromosomal instability (CIN), is common in cancer. Increasing CIN above a maximally tolerated threshold leads to cell death due to loss of essential chromosomes. Here, we show in two tissue contexts that otherwise isogenic cancer cells with higher levels of CIN are more sensitive to ionizing radiation, which itself induces CIN. CIN also sensitizes HPV-positive and HPV-negative head and neck cancer patient derived xenograft (PDX) tumors to radiation. Moreover, laryngeal cancers with higher CIN prior to treatment show improved response to radiation therapy. In addition, we reveal a novel mechanism of radiosensitization by docetaxel, a microtubule stabilizing drug commonly used in combination with radiation. Docetaxel causes cell death by inducing CIN due to abnormal multipolar spindles rather than causing mitotic arrest, as previously assumed. Docetaxel-induced CIN, rather than mitotic arrest, is responsible for the enhanced radiation sensitivity observed in vitro and in vivo, challenging the mechanistic dogma of the last 40 years. These results implicate CIN as a potential biomarker and inducer of radiation response, which could provide valuable cancer therapeutic opportunities. Statement of SignificanceCancer cells and laryngeal tumors with higher chromosome missegregation rates are more sensitive to radiation therapy, supporting chromosomal instability as a promising biomarker of radiation response.

cancer biology↗