Biology subjects

Beausejour, C.

Publications and source records attributed to Beausejour, C..

10 recordsLinked to original sources

bioRxiv2026

Senescent fibroblasts interfere with the tumor immune response in humanized models by inducing neutrophil extracellular traps

Neutrophils are known to promote tumor progression and metastasis, in part through the release of extracellular traps (NETs), a phenomenon associated with poor prognosis in patients. Here, we demonstrate that senescent fibroblasts, via their senescence-associated secretory phenotype (SASP), promote the recruitment of CD33+ myeloid cells and impair the tumor immune response in an orthotopic humanized mouse lung cancer model. Mechanistically, we found that therapy-induced senescence triggers the formation of NETs, which interfere with immune cell infiltration in tumor spheroids. This phenotype was reversible upon treatment with DNAse I or Reparixin, an inhibitor of the action of CXCL8/IL-8 and CXCL1/GRO1, two key SASP factors. Furthermore, we show that senescence-induced NETs favor lung metastasis in a humanized mouse model, a phenotype that was inhibited by DNase I treatment. Our findings provide critical insights into the complex interplay between cellular senescence, NETosis, and the tumor immune response, highlighting another mechanism by which senotherapies can improve cancer treatments.

cell biology↗

bioRxiv2025

Off-the-Shelf Engineered Liver Tissue Reverses Acute Liver Failure Without Immunosuppression

There is an urgent need for effective solutions to replace liver functions in patients with acute liver failure (ALF). We describe here a human engineered liver tissue composed of induced pluripotent stem cell (iPSC)-derived liver organoids encapsulated within a non-degradable biomaterial. Unlike most stem cell-derived products, this encapsulated liver tissue (ELT) achieves functional maturation during manufacturing. When transiently implanted into the peritoneal cavity of immunocompetent mice with ALF, the human ELT improves survival, treats hepatic encephalopathy and promotes liver regeneration, without requiring immunosuppression. Based on robust processes and designed to overcome challenges such as foreign body reaction, loss of function and cryopreservation, the ELT does not require vascularization and provides immediate and long-lasting functional replacement. Once the liver regenerated, the ELT is explanted, leaving the subjects cured. Macroencapsulation prevents rejection by shielding the organoids from the host immune system, and minimizes the risk of tumorigenicity. The data shown demonstrate the ELTs potential to be developed into a safe and effective off-the-shelf treatment that, if validated in upcoming clinical trials, could replace liver transplantation for many patients with ALF.

bioengineering↗

bioRxiv2024

Senescent fibroblasts support tumor growth by inducing immune cell death in humanized models

Syngeneic mouse tumor models have shown that senescence influences the tumor immune response in multiple ways, including the induction of an immunosuppressive microenvironment or the promotion of immune cell recruitment. Yet, the impact of senescence on the tumor immune response in a humanized setting remains largely unexplored. To address this, we employed tumor spheroids and mice bearing tumors immunogenic to human immune cells derived from the same donor. We found that senescent fibroblasts exert a dual effect by enhancing the recruitment of immune cells into the tumor microenvironment while simultaneously promoting the apoptosis of T and NK cells. Mechanistically, we demonstrate that this apoptosis is primarily due to increased Fas ligand (FasL) expression on the surface of senescent fibroblasts. Deletion of FasL on fibroblasts was sufficient to prevent immune cell death and increase tumor cell killing. Our results highlight the importance of evaluating the impact of therapy-induced senescence in humanized models to understand and predict the outcome of cancer treatments.

cancer biology↗

bioRxiv2022

Nuclear Location Bias of HCAR1 Drives Cancer Malignancy through Numerous Routes

The involvement of G-Protein-Coupled Receptors (GPCR) location bias in diverse cellular functions and their misregulation in pathology is an underexplored territory. HCAR1, a GPCR for lactate is linked to cancer progression, mainly due to Warburg effect, but its mechanism of action remains elusive. Here, we show HCAR1 has a nuclear localization, capable of signaling intranuclearly to induce nuclear-ERK and AKT phosphorylation concomitant with higher cancer cell proliferation and survival. We determine its nuclear interactome, proving its involvement in protein-translation and DNA-damage repair. Nuclear HCAR1 (N-HCAR1) directly interacts with chromatin/DNA promoting expression of genes involved in cellular migration. Notably, we show N-HCAR1 particularly regulates a broader transcriptomic signature than its PM counterpart, emphasizing on the facts that functional output of N-HCAR1 is larger than PM localized HCAR1. Our study presents several unprecedented processes by which a GPCR through location-biased activity regulate various cellular functions and how cancer cells exploit these.

cell biology↗

bioRxiv2022

Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1.

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis.

cell biology↗

bioRxiv2021

Autologous humanized mouse models of iPSC-derived tumors allow for the evaluation and modulation of cancer-immune cell interactions

Modeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or iPSC-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that either fibroblastic, hepatic or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cell suggesting rapid establishment of an immunosuppressive microenvironment. Inhibition of PD-1 by Nivolumab in humanized mice resulted in an increased immune cell infiltration and a slight decrease in tumor growth. We expect these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types. SIGNIFICANCE STATEMENTPreclinical models capable of providing an environment where human tumors are confronted with autologous immune cells are not easily accessible and limit drug development. As an alternative we generated genetically-defined tumor cell lines from primary and iPSC-derived cells for the evaluation of cancer-immune cell interactions in autologous humanized mice.

cancer biology↗

bioRxiv2019

NK cells prevent the formation of teratomas derived from human induced pluripotent stem cells

The safe utilization of induced pluripotent stem cell-derivatives in clinic is tributary to the complete elimination of the risk of forming teratomas after transplantation. The extent by which such a risk exists in immune competent hosts is mostly unknown. Here, using humanized mice reconstituted with fetal hematopoietic stem cells and autologous thymus tissue (Hu-BLT) or following the adoptive transfer of peripheral blood mononuclear cells (PBMCs) (Hu-AT), we evaluated the capacity of immune cells to prevent or eliminate teratomas derived from human induced pluripotent stem cells (hiPSCs). Our results showed that the injection of hiPSCs failed to form teratomas in Hu-AT mice reconstituted with allogeneic or autologous PBMCs or purified NK cells alone. However, teratomas were observed in Hu-AT mice reconstituted with autologous PBMCs depleted from NK cells. In line with these results, Hu-BLT which do not have functional NK cells could not prevent the growth of autologous teratomas. Finally, we found that established teratomas were not targeted by NK cells and instead were efficiently rejected by allogeneic but not autologous T cells in Hu-AT mice. Overall, our findings suggest that autologous hiPSC-derived therapies are unlikely to form teratomas in the presence of NK cells.

cell biology↗

bioRxiv2019

The tumor immune response is not compromised by mesenchymal stromal cells in humanized mice

Therapeutic uses of mesenchymal stromal cells (MSCs) have emerged over the past decade. Yet, their effect on tumor growth remains highly debated, particularly in an immune competent environment. Here, we wanted to investigate the impact of human umbilical cord MSCs (hUC-MSCs) on tumor growth in humanized mice generated by the adoptive transfer of peripheral blood mononuclear cells (Hu-AT) or the co-transplantation of hematopoietic stem cells and human thymic tissue (Hu-BLT). Our results showed that the growth and immune rejection of engineered human tumors was not altered by the injection of hUC-MSCs in immune-deficient or humanized mice respectively. This was observed whether tumor cells were injected subcutaneously or intravenously and independently of the injection route of the hUC-MSCs. Moreover, only in Hu-BLT mice did hUC-MSCs have some effects on the tumor immune infiltrate, yet without altering tumor growth. These results demonstrate that hUC-MSCs do not promote tumor growth and neither do they prevent tumor infiltration and rejection by immune cells in humanized mice.

cell biology↗

bioRxiv2019

Immune Responses to Human Induced Pluripotent Stem Cells and their Derived Myogenic Progenitors Are Mediated by Different Mechanisms in Humanized Mice

It is still unclear if immune responses will compromise the large scale utilization of cell therapies derived from human induced pluripotent stem cells (hiPSCs). To answer this question, we used humanized mouse models and evaluated the engraftment in skeletal muscle of myoblasts derived either directly from a muscle biopsy or differentiated from hiPSCs or fibroblasts. Our results showed that while allogeneic grafts were rejected, engraftment of autologous cells was tolerated, indicating reprogramming and differentiation procedures are not immunogenic. We also demonstrated that hiPSC-derived myogenic progenitors, in opposition to hiPSCs, are not targeted by natural killer (NK) cells both in vitro and in vivo. Yet, adoptive transfer of NK cells can prevent the formation of hiPSC-derived teratoma. Overall, our findings suggest that hiPSC-derived muscular therapies will be tolerated in presence of a competent human immune system and highlight the risk of forming a teratoma if using partially differentiated autologous human cells. HighlightsO_LIhiPSC-derived myofibers are tolerated in autologous humanized mouse models C_LIO_LIInfiltration of autologous T cells is not predictive of successful skeletal muscle engraftment C_LIO_LIAdoptive transfer of NK cells prevents the formation of hiPSCs derived teratomas C_LIO_LINK cells are unable to reject established teratomas C_LI

cell biology↗

bioRxiv2018

Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases

Targeting MYC oncogene remains a major therapeutic goal in cancer chemotherapy. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment exhibit anticancer selectivity towards high MYC expressing leukemic cell lines and leukemia stem cells. At a clinically relevant concentration, proscillaridin induced a rapid downregulation of MYC protein level, due to a significant decrease in MYC protein half-life. Proscillaridin treatment induced a downregulation of gene sets involved in MYC pathway, and a concomitant upregulation of genes involved in hematopoietic differentiation. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (K9, K14, K18 and K27) and in non-histone proteins such as MYC, MYC target proteins, and a series of histone acetylation regulators. Loss of lysine acetylation correlated with a rapid downregulation of histone acetyltransferase protein levels, involved in histone and MYC acetylation (CBP, P300, GCN5, TIP60, and MOZ), preferentially in MYC overexpressing leukemia as compared to other cancer cells. These results support the repurposing of proscillaridin in MYC overexpressing leukemia and propose a novel strategy to target MYC in cancer.

pharmacology and toxicology↗