Biology subjects

Jacquel, A.

Publications and source records attributed to Jacquel, A..

6 recordsLinked to original sources

bioRxiv2025

Non-canonical caspase-8 activation by cathepsin B drives anti-inflammatory human macrophage polarization

Anti-inflammatory monocyte-derived macrophages are essential to maintain tissue homeostasis but can also contribute to disease progression, notably in cancer and fibrosis. Deciphering the signaling pathways that govern their generation could therefore unlock new therapeutic opportunities. Here we uncover a previously unrecognized, non-apoptotic function of caspase-8 in driving both monocyte-to-macrophage differentiation and anti-inflammatory macrophages polarization. We identified cathepsin B as a novel upstream activator of caspase-8 activation through a non-canonical cleavage mechanism, conferring to caspase-8 an original activity profile distinct from its apoptotic role. Disruption of this cathepsin-B-caspase-8 axis, either genetically or pharmacologically, not only impairs the generation of anti-inflammatory macrophages but also reprograms these cells towards a pro-inflammatory phenotype. Our findings position the cathepsin-B-caspase-8 axis as a critical regulatory node in macrophage fate decisions and a promising target for therapeutic reprogramming of human macrophages in cancer, inflammation and fibrotic diseases.

immunology↗

bioRxiv2025

CSF1R regulates monocyte subset differentiation and intracellular metabolism.

Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6Chigh) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6Clow) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6Clow monocytes in part by blunting differentiation of Ly6Chigh monocytes. Based upon lineage-specific deletion of GFPT1 (Glutamine-Fructose-6-Phosphate Transaminase 1), the hexosamine biosynthetic pathway (HBP) is identified as a novel regulator of CSF1R expression and monocyte subset diversity. Our findings provide new insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.

immunology↗

bioRxiv2025

Enhanced efficacy of a specific HDAC3 inhibitor in combination with 5-Azacitidine against diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) refers to an aggressive lymphoma that arises from germinal center (GC) B-cells, which differentiate into plasma cells (PC) to produce high affinity antibodies. 40% of DLBCL patients relapse or are refractory to the conventional immunochemotherapy treatment, usually with fatal consequences. Therefore, there is an unmet critical need to find more targeted therapies for DLBCL. DLBCL are characterized by profound alterations in the epigenome, which are correlated with poor survival. While epigenetic therapies are used as anti-cancer treatments, their full potential has not been achieved, mainly because of their limited efficacy when used as monotherapies and recurrent side effects associated with their low specificity. The abnormal epigenetic landscape of DLBCL tumors is associated with a blockade in GC exit and differentiation programs, which are regulated by the transcription factor BCL6. This aberrant repression of BCL6-target genes is mediated at least by two epigenetic mechanisms: 1) increased DNA methylation and 2) loss of acetylation of the lysine 27 of histone 3 (H3K27ac)-through recruitment of histone deacetylase 3 (HDAC3). Therefore, we investigated the efficacy against DLBCL of a novel combinatorial epigenetic therapy using the hypomethylating agent (HMA) 5-Azacitidine (5-Aza) and a specific HDAC3 inhibitor (HDAC3i). We found that treatment with 5-Aza and HDAC3i had a potent synergistic anti-tumor activity in vitro and in vivo, which was superior to the effect of each single drug or 5-Aza combined with non-specific HDACi and, importantly, was not associated with toxicity in normal cells. We also demonstrated that the combined 5-Aza and HDAC3i treatment induced the epigenetic remodeling of DLBCL cells, which resulted in a more potent re-expression of PC differentiation genes, including XBP1 and ATF4, compared to each drug used as single agents. Our results highlight the importance of targeting multiple layers of the epigenome to maximize the efficacy of epigenetic-based therapies.

cancer biology↗

bioRxiv2024

AML patient blasts exhibit polarization defect upon interaction with bone marrow stromal cells.

Hematopoietic stem and progenitor cells (HSPCs) establish specific interactions with bone marrow stromal cells, leading to their polarization. Given the role of cell polarity in protection against tumorigenesis and the importance of the niche in hematological disorders such as acute myeloid leukemias (AMLs), we investigated the polarization capacities of leukemic blasts from patients. Using engineered micro-niches and centrosome position with respect to the contact site with stromal cells as a proxy for cell polarization, we showed that AML cell lines and primary cells from AML patient blasts were unable to polarize in contact with healthy stromal cells. In return, exposure to AML patient-derived stromal cells compromised the polarization of healthy adult HSPCs and AML blasts from patients. Using live cell imaging in engineered "bone-marrow-on-a-chip", we further revealed that stromal cells from a leukemic niche increased the migration speed and distance of healthy HSPCs and AML blast as compared to their behavior in contact with healthy stromal cells. The results collectively demonstrated the respective influences of intrinsic AML blast transformation and extrinsic contact with AML stromal cells on the defective polarization of AML blast. They suggested that leukemic progression is associated with cell polarization defects and proposed new methodological approaches to investigate this relationship in AML progression.

cancer biology↗

bioRxiv2024

Dual targeting of GPX4 and TXNRD1 triggers eradication of AML cells through induction of apoptosis and ferroptosis

MyeloDysplastic Syndromes (MDS) are a group of heterogeneous hematological disorders characterized by bone marrow failure and abnormal hematopoietic cell expansion, often progressing to acute myeloid leukemia (AML). Current treatments for AML and high-risk MDS have limited efficacy, requiring the exploration of new therapeutic approaches. Recent research highlighted the potential of inducing cell death through ferroptosis, either independently or alongside traditional chemotherapy, as promising approaches for treating MDS/AML cells. We described here two novel compounds, HA344 and #231, capable of targeting both ferroptosis and apoptosis, leading to the effective eradication of cell lines and primary blasts from MDS/AML patients, while sparing normal hematopoietic cells. RNASeq analysis identified oxidation reduction and apoptotic processes as highly significant induced pathways in two different AML cell lines. Using click-chemistry approaches coupled to mass spectrometry, we identified glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1) as the main targets of HA344 and #231 in a large panel of AML cells. Accordingly, both compounds inhibited GPX4 and TXNRD1 activity in the micromolar range and triggered GPX4 degradation. Moreover, using recombinant GPX4 carrying or not a selenium (GPX4-Se and GPX4-S), we confirmed by mass spectrometry that HA344 and #231 bind more efficiently GPX4-Se than GPX4-S. In conclusion, these compounds might represent a new pharmacological approach in the treatment of MDS and AML, offering a potential avenue for future therapies.

biochemistry↗

bioRxiv2022

HSPA8 chaperone complex drives chaperone-mediated autophagy regulation in acute promyelocytic leukemia differentiation

Acute myeloid leukemia (AML) is a cancer of the hematopoietic system characterized by the hyperproliferation of undifferentiated cells of the myeloid lineage. While most of AML therapy are focusing on tumor debulking, all-trans retinoic acid (ATRA) induces differentiation in acute promeylocytic leukemia (APL) a particular subtype. Macroautophagy has been extensively investigated in the context of various cancers and is often dysregulated in AML where it can have context-dependent pro- or anti-leukemogenic effects. On the contrary, the implications of chaperone-mediated autophagy (CMA) on the pathophysiology of diseases are still being explored and its role in AML has remained elusive. To answer our questions we took advantages of human AML primary samples and databases. Furthermore, we used ATRA-sensitive (NB4) and -resistant (NB4-R1) cells to further dissect a potential function for CMA in ATRA-mediated neutrophil differentiation. NB4-R1 cells are unique in that they do respond to retinoic acid transcriptionally, but do not mature in response to retinoid signaling alone unless maturation is triggered by adding cAMP. Here, we report that CMA related mRNA transcripts are higher expressed in immature hematopoietic cells as compared to neutrophils. In line, lysosomal degradation of mCherry-KFERQ CMA reporter decreases during ATRA-induced differentiation of APL cells. On the other hand, using NB4-R1 cells we found that macroautophagy flux primed the ATRA resistant NB4-R1 cells to differentiate upon ATRA treatment, but reduced association of LAMP-2A and HSPA8 is necessary for complete neutrophil maturation. Accordingly, depletion of HSPA8 attenuated CMA activity and facilitated APL differentiation. In contrast, maintaining high CMA activity by ectopic expression of LAMP-2A impeded APL differentiation. Overall, our findings demonstrate that both normal and APL neutrophil differentiation require CMA downregulation and this pathway is predominantly dependent on HSPA8 assisted by other co-chaperones.

cancer biology↗