Biology subjects

Nersesian, S.

Publications and source records attributed to Nersesian, S..

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

Persistent glycolysis defines the foreign body response to polymeric implants.

Non-degradable polymeric implantable medical devices are a mainstay of modern healthcare but can frequently lead to severe complications. These complications are largely attributable to the foreign body response (FBR), which is characterized by excessive inflammation and fibrosis in response to implanted materials. The pathologic mechanisms underpinning the FBR remain elusive; however, metabolism is increasingly regarded as a critical regulator of innate immune function. We conducted comprehensive metabolic profiling of implant-associated macrophages and multinucleated giant cells in response to the subcutaneous implantation of clinically relevant implantable materials in a mouse model of implant fibrosis. Leveraging novel metabolic characterization methods for analysis of both metabolic dependence and enzyme expression in heterogeneous peri-implant tissues, we demonstrate that peri-implant macrophages are glycolytic at least up to six weeks post-implantation. Glycolytically dependent peri-implant macrophages expression of glucose transporter 1 (GLUT1) increased temporally and with proximity to the implant-tissue interface. Paired rate-limiting metabolic enzyme expression analysis showed notable increases in biosynthetic pathways (G6PD and ACC1), matched with increased mitochondrial staining intensity in GLUT1Hi cells at chronic timepoints, which were not notable at early timepoints. Notably, we identified a glycolytic dependence of multinucleated macrophages associated with polymeric materials: these cells expressed higher levels of GLUT1 than mononuclear macrophages of comparable metabolic phenotype. Our findings highlight GLUT1-dependent glycolysis as the definitive metabolic system used by peri-implant macrophages and multinucleated cells in the FBR, highlighting this pathway as a potential target for the development of novel therapeutic approaches.

immunology↗

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↗

bioRxiv2019

Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer.

Poor response to platinum/taxane-based chemotherapy has remained a major hurdle in the management of high grade serous carcinoma of the ovary (HGSC). Recurrent HGSC is often treated with liposomal doxorubicin as a second line chemotherapy. Unfortunately, HGSC patients have not benefited from immunotherapies targeting the PD-1/PD-L1 immune checkpoint axis. In a pre-clinical study evaluating the efficacy of a \"Stimulator of Interferon Genes\" (STING) agonist, we demonstrated the synergistic potential of STING pathway activation in enhancing response to carboplatin chemotherapy and sensitization to PD-1 immune checkpoint blockade (ICB). Since carboplatin and doxorubicin exhibit distinct immunogenic cell death (ICD) inducing potential, we investigated the chemotherapy specific effect in the magnitude of response to exogenous STING pathway activation. Immunocompetent C57/BL6 mice were implanted with ID8-Trp53-/- cells followed by treatment with carboplatin or doxorubicin. Towards rationalized addition of STING agonist with or without PD-L1 blockade, we first determined the expression of 60 known ICD associated genes at an early time point following the initial treatment with carboplatin or doxorubicin with or without STING agonist. Doxorubicin treated tumours showed significantly higher expression of ICD genes, Cxcl10, Cd274, Isg15, Psmb9 and Calr. Expression changes were further amplified following the addition of STING agonist. Significantly higher expression of Cxcl10 and Isg15 were observed in the doxorubicin + STING agonist treated mice compared to carboplatin + STING agonist combination. Interestingly, Ccl5 gene expression was higher in the tumours from carboplatin or carboplatin and STING agonist combination treated mice compared to those treated with doxorubicin. Plasma cytokine analysis showed distinct profiles of CXCL10, CCL5, MCP-1 and IL6 post treatment with each chemotherapy type. Doxorubicin monotherapy treated mice showed significantly longer overall survival compared to their carboplatin counterparts with further increases following addition of either STING agonist or PD-L1 ICB. However, despite the stronger ICD inducing ability of doxorubicin, overall survival of mice treated with carboplatin + STING agonist + PD-L1 ICB was the longest. Findings from our pre-clinical study provide novel insights for rationalized combinations of immune sensitizing agents such as STING pathway activators to improve response of HGSC patients to chemotherapy and ICB in the primary and recurrent settings.

cancer biology↗