Biology subjects

Abou-Hamad, J.

Publications and source records attributed to Abou-Hamad, J..

4 recordsLinked to original sources

bioRxiv2026

Tumour architecture shapes polarized epithelial states that predict survival in high-grade serous ovarian cancer

Epithelial heterogeneity defines high-grade serous ovarian carcinoma (HGSC), yet principles that generate this diversity within and across tumours remain unclear. Integrating single-cell RNA sequencing (scRNA-seq) data from 13 studies (1,980,703 cells, 371 samples), we resolve a dominant axis of secretory cell polarization spanning proliferative, progenitor-like SecA cells and quiescent SecB cells expressing a mucosal injury response program. Targeted spatial transcriptomics across 8 whole HGSC tissues and a 97-patient tissue microarray shows this axis is spatially deterministic: tumour architecture shapes a hypoxic gradient along which SecB cells localize to avascular, luminal regions, where HIF/NF-{kappa}B-driven survival and glycolysis displace the mitogenic signalling of SecA. Within this niche, SecB cells rewire adhesion, ECM-remodelling, and immune-regulatory programs. Transcriptionally reprogrammed macrophages are enriched in this niche, while lymphocytes are excluded or dysfunctional. These cells assemble a coordinated multicellular niche poised for dissemination. SecB cells are enriched both in ascites and after chemotherapy, and are progressively lost in patient-derived organoids, only partially restored by IFN{gamma}, suggesting SecB is environmentally programmed rather than clonally fixed. SecB proportion independently predicts worse overall (HR = 1.31, p = 0.023) and progression-free survival (HR = 1.28, p = 0.011). Tumour architecture is thus a primary axis of malignant identity in HGSC, coupling microenvironment, cell state, and immune niche to clinical outcomes.

cancer biology↗

bioRxiv2025

Loss of Sox10 in a HER2+ model prevents tumor initiation and induces luminal-to-basal reprograming in cancer cells.

The SRY-HMG-Box transcription factor SOX10 plays a critical role in neural crest development, but its function in epithelial tumorigenesis remains unclear. Here, we identify SOX10 as a key regulator of tumor-initiating activity in Neu-driven mammary cancers. Genetic ablation of Sox10 in the luminal compartment of MMTV-Neu (NIC) mice resulted in delayed but normal mammary gland development. Sox10 deletion resulted in a reduction in mammary progenitors and tumor initiating activity with a complete loss of tumor initiation in Sox10-deficient luminal cells. CRISPR/Cas9-mediated Sox10 inactivation in Neu-transformed tumor cells led to diminished self-renewal in mammosphere assays, markedly impaired growth in orthotopic transplant models and profoundly reduced lung colonization following tail vein injection, suggesting a depletion of cancer stem cell activity. Transcriptomic profiling revealed that Sox10-deficiency in Neu+ tumor cells induces a luminal-to-basal/stem-like shift and the downregulation of several genes associated with genetic networks regulating stemness. Collectively, these findings demonstrate that Sox10 is required for a permissive luminal cell state for Neu-driven tumor initiation and that it is critical for cancer stem cell activity and the establishment of metastases. SignificanceThe Sox10 transcription factor is critical for mammary stem cell function and plasticity. Animal studies suggest that different subtypes of breast cancers arise from luminal epithelial cells and hypothesized the implication of luminal stem cells in breast cancer initiation. We show that Sox10 deletion in the luminal compartment of adult female mice abrogates tumor initiation. Sox10 inactivation impairs tumor cell growth, dissemination and reprograms luminal Neu+ tumor cells to a basal phenotype. Our data supports a model whereby luminal progenitors are required for tumor initiation, self-renewal and growth at distant sites. The findings suggest that therapies aimed at interfering with Sox10 activity or expression might be beneficial in the treatment of breast cancers.

cancer biology↗

bioRxiv2024

LAG3 marks activated but hyporesponsive NK cells.

Natural Killer (NK) cells are critical for immunosurveillance yet become dysfunctional in contexts such as chronic stimulation by viral infections or cancer. This phenomenon is similar to T cell exhaustion but less well characterized, which limits therapeutic interventions. As shown for T cells, NK cells often display an increased expression of immune checkpoint proteins (ICP) following chronic stimulation, and ICP blockade therapies are currently being explored for several cancer types, which have remarkable patient benefits. Nevertheless, the nature of ICP expression in NK cells is still poorly documented. In this study, we aimed to identify the conditions that lead to and the phenotype of immune checkpoint LAG3 (Lymphocyte-activation gene 3) expressing NK cells. Using various experimental models, we found that LAG3 is expressed by murine NK cells upon activation in different contexts, including in response to cancer and acute viral infections. LAG3 marks a subset of immature, proliferating and activated cells, which, despite activation, have a reduced capacity to respond to a broad range of stimuli. Further characterization also revealed that LAG3+ NK cells exhibit a transcriptional signature similar to that of exhausted CD8+ T cells. Taken together, our results support the use of LAG3 as a marker of dysfunctional NK cells across diverse chronic and acute inflammatory conditions.

immunology↗

bioRxiv2022

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway.

Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced infection with oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 suppressed type I interferon by promoting a metabolic shift characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD-L1-expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials. Once sentence summaryPD-L1 promotes oncolytic virus efficacy.

cancer biology↗