Biology subjects

Bisteau, X.

Publications and source records attributed to Bisteau, X..

5 recordsLinked to original sources

bioRxiv2026

TRMT10A deficiency and tRNA fragmentation disrupt human pancreatic β-cell identity and insulin maturation

Mutations in the tRNA-modifying enzyme TRMT10A cause a rare monogenic syndrome characterized by early-onset diabetes and neurodevelopmental defects, yet the molecular mechanisms underlying TRMT10A diabetes remain unclear. Using human TRMT10A-deficient (knockout and mutant) induced pluripotent stem cells (iPSCs) differentiated into islet-like aggregates and TRMT10A-silenced EndoC-{beta}H1 human {beta}-cells, we show that TRMT10A deficiency impairs {beta}-cell differentiation, insulin content and glucose-stimulated insulin secretion while inducing widespread transcriptional alterations. These defects are accompanied by oxidative stress, diminished antioxidant capacity, and defective proinsulin processing driven by reduced PCSK1 expression. Mechanistically, the loss of TRMT10A promotes tRNA fragmentation and the generation of fragments derived from the 5 end of tRNAGln-CTG (tDRGln-CTG) that interact with hnRNPM. Our data support the existence of a previously unrecognized hnRNPM-PTBP1 interaction in human {beta}-cells and suggest that this complex may contribute to the regulation of PCSK1 mRNA stability and/or translation. Furthermore, through its interaction with hnRNPM, tDRGln-CTG may alter the function of the complex thereby contributing to reduced PCSK1 expression, defective proinsulin processing, and impaired insulin content. Our findings link tRNA fragmentation, RNA-binding protein networks and insulin maturation, positioning TRMT10A as a critical regulator of {beta}-cell identity and function and uncovering a novel mechanism of {beta}-cell failure in the pathogenesis of diabetes.

molecular biology↗

bioRxiv2026

Cisplatin-Induced Plasticity Drives Cross-Resistance to CDK4/6 Inhibitors and Reveals Targetable Vulnerabilities Through HDAC Inhibition in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal cancer cases worldwide and carries a poor prognosis, with overall survival below 20%. Chemotherapy remains the standard of care, yet acquired resistance is a critical barrier and the programs that establish and stabilize it are still poorly defined. Using an in vitro model of cisplatin resistance, we show that sustained platinum exposure does not drive a single, uniform resistant state but a continuum of adaptive transcriptional states. Most resistant clones presented a drug-tolerant persister (DTP)-like phenotype with stemness traits and slow-cycling behaviour. The DTP phenotype persisted after cisplatin withdrawal and was accompanied by markers of resistance, suggesting consolidation into a stable, acquired-resistance state. Unexpectedly, the effect of this reprogramming extended beyond cisplatin. Resistant clones displayed impaired cytostatic control and failed to suppress cell cycle programs upon CDK4/6 inhibition (CDK4/6i), revealing collateral cross-resistance. Multiomic profiling revealed an attenuation of the immune and inflammatory signaling expected from CDK4/6i, upregulation of immune-evasive markers and a dysregulated IFN pathway activation at baseline in cisplatin-resistant clones, reflecting an immune-evasive state consequent to cisplatin-induced reprogramming. A signature-based approach identified HDAC inhibitors as candidates for reversing resistance, and functional validation confirmed that HDACi combined with cisplatin fully restored parental-level sensitivity while also enhancing CDK4/6i efficacy, supporting epigenetic reprogramming as a strategy to counteract cross-resistance. Together, our findings define cisplatin resistance in ESCC as a reversible, epigenetically encoded and immune-evasive state, and provide a mechanistic rationale for HDACi-based combinations to restore sensitivity to both cisplatin and CDK4/6 inhibitors. Statement of SignificanceSustained cisplatin exposure drives esophageal squamous cell carcinoma toward a drug-tolerant persister-like, immune-evasive state that survives drug withdrawal and confers cross-resistance to CDK4/6 inhibition. HDAC inhibition reverses this state, restoring sensitivity to both agents and synergizing in chemotherapy-naive cells, supporting epigenetic intervention early in treatment.

cancer biology↗

bioRxiv2025

CDK4/6 Inhibition Uncovers Subtype-Specific Vulnerabilities and Immune-Related Responses in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (eSCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors such as nivolumab, have shown clinical benefit, particularly in patients with high PD-L1 expression, this subgroup represents only a small fraction of eSCC cases. CDK4/6 inhibitors such as palbociclib have only been tested as second-line agents in eSCC, often in combination with EGFR inhibitors, with minimal benefit. Our study evaluates palbociclib as a first-line therapy in treatment-naive eSCC models. Using a panel of 22 eSCC cell lines with integrated multi-omics and phenotypic assays, we identified three response subtypes, resistant, delayed and arrested, correlated to Rb-pathway status. Interestingly, in delayed responders, palbociclib induced replication stress, DNA damage, and unprotected micronuclei enriched for cGAS, triggering activation of interferon-stimulated genes. Consistent with this, palbociclib enhanced immune cell infiltration in delayed eSCC spheroids within a preclinical vascularized 3D microfluidic system. Our study demonstrates that first-line palbociclib treatment unmasks intrinsic vulnerabilities in the CDK4/6-Rb axis and triggers innate immune activation in molecularly defined eSCC. Using a translationally relevant 3D vascularized microfluidic system, we provide evidence that early CDK4/6 inhibition not only stall cancer cell growth but also promotes immune cells recruitment. In conclusion, our study identifies palbociclib as a viable first-line therapeutic candidate in selected eSCC patients and uncover its immunomodulatory potential. SignificanceThese findings support further research into CDK4/6 inhibition as first-line treatment for eSCC and highlight its potential to influence the tumor immune microenvironment in ways that could improve responses to combination therapies.

cancer biology↗

bioRxiv2022

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of malignant pleural mesotheliomas to CDK4/6 inhibition

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a panel of 28 MPM cell lines, including 19 patient-derived cell lines, using a variety of approaches including RNA-sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 over-expression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was also irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPM tumors indicating their intrinsic sensitivity to CDK4/6 inhibitors. The absence of this phosphorylation in some highly proliferative MPM tumors was linked to partial deletions of RB1, leading to very high p16 (CDKN2A) expression. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment, in monotherapy or combination therapy.

cancer biology↗

bioRxiv2022

Zebrafish Galectin 3 binding protein (Lgals3bp) is the target antigen of the microglial 4C4 monoclonal antibody

BackgroundTwo decades ago, the fish-specific monoclonal antibody 4C4 was found to be highly reactive to zebrafish microglia, the macrophages of the central nervous system. This has resulted in 4C4 being widely used, in combination with available fluorescent transgenic reporters to identify and isolate microglia. However, the target protein of 4C4 remains unidentified, which represents a major caveat. In addition, whether the 4C4 expression pattern is strictly restricted to microglial cells in zebrafish has never been investigated. ResultsHaving demonstrated that 4C4 is able to capture its native antigen from adult brain lysates, we used immunoprecipitation/mass-spectrometry, coupled to recombinant expression analyses, to identify its target. The cognate antigen was found to be a paralog of Galectin 3 binding protein (Lgals3bpb), known as MAC2-binding protein in mammals. Notably, 4C4 did not recognize other paralogs, demonstrating specificity. Moreover, our data show that Lgals3bpb expression, while ubiquitous in microglia, also identifies leukocytes in the periphery, including populations of gut and liver macrophages. ConclusionsThe 4C4 monoclonal antibody recognizes Lgals3bpb, a predicted highly glycosylated protein whose function in the microglial lineage is currently unknown. Identification of Lgals3bpb as a new pan-microglia marker will be fundamental in forthcoming studies using the zebrafish model.

immunology↗