Biology subjects

Caballe, A.

Publications and source records attributed to Caballe, A..

4 recordsLinked to original sources

bioRxiv2026

MET inhibition exploits conserved regulatory dependencies in malignant rhabdoid tumors

Malignant rhabdoid tumors (MRTs) are lethal, yet genomically simple childhood cancers characterised by universal SWI/SNF dysregulation. Despite this shared molecular framework, the regulatory programs sustaining MRTs and how they wire actionable dependencies, remain poorly defined. Here, we integrated single-cell multi-omic profiling and spatial transcriptomics across anatomically and molecularly diverse MRTs, generating a comprehensive multimodal MRT dataset at single-cell resolution. We leveraged this resource to identify candidate tumor-specific dependencies, which were subsequently functionally validated in vitro and in vivo in matched patient-derived models. We found that distinct malignant subpopulations are spatially patterned in complex environmentally shaped topologies, consistent with reciprocal interactions with stromal and immune compartments contributing to intratumoral transcriptional diversity. We identified recurrent transcriptional metaprograms conserved across patients and molecular subtypes, including a previously undescribed shared core rhabdoid program, as well as a metaprogram characterized by extracellular matrix interactions, and preferentially localized in tumor-stroma intermixed neighborhoods, supporting identification of niche conditioning cues. Mechanistically, we identified regulatory wiring driving these metaprograms, with the core shared rhabdoid programme coordinated by a circuit centred on TCF12, ZNF148 and CHD2. Guided by target nominations from our integrated analyses, we performed a curated drug screen using patient-derived MRT models and validated HGF/MET signaling as a selective vulnerability in extrarenal rhabdoid tumors. Pharmacologic MET inhibition was cytotoxic in sensitive models and induced a complete response in vivo using a clinically approved compound. Importantly, MET expression in primary tumors correlated with response, supporting biomarker-guided patient stratification for immediate clinical translation. Collectively, our findings define the molecular architecture of MRTs, reveal conserved regulatory programs beyond anatomical and molecular subtypes, and highlight a targetable signaling axis with immediate translational potential, establishing a framework for precision therapy in this lethal pediatric malignancy.

cancer biology↗

bioRxiv2025

Structural insights into mitotic-centrosome assembly

Centrosomal material assembles rapidly in mitosis. In Drosophila, the coiled-coil protein Cnn forms a scaffold that recruits PCM clients; in C.elegans, SPD-5 plays an analogous role. Here we show that full-length Cnn and SPD-5 can both form spherical condensates in vitro, but that the interactions driving their assembly into scaffolds inside cells appear to diverge. We show that the Cnn PReM adopts a helical hairpin fold that autoinhibits CM2 binding but that phosphorylation appears to increase hairpin breathing to permit CM2 engagement and robust scaffold assembly. Phospho-blocking mutations prevent PReM-CM2 interactions and scaffold formation, whereas phospho-mimetic substitutions partially restore function. The human homologue CDK5RAP2 contains a CM2 domain that can partially substitute for fly CM2 in vivo and we identify a candidate CDK5RAP2 PReM region that forms macromolecular networks with human CM2 in vitro. By contrast, the putative PReM and CM2 regions of SPD-5 cannot substitute for their equivalent fly domains and they do not interact detectably, suggesting a distinct assembly mechanism in worms despite conserved PLK1-dependent control of PCM growth.

cell biology↗

bioRxiv2022

Induction of senescence renders cancer cells highly immunogenic

Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy. STATEMENT OF SIGNIFICANCEOur study shows that senescent cells are endowed with a high immunogenic potential, superior to the gold standard of immunogenic cell death. The induction of senescence in cancer cells can be exploited to develop efficient and protective CD8-dependent anti-tumor immune responses.

cancer biology↗

bioRxiv2021

A dynamic equilibrium between TTP and CPEB4 controls mRNA stability and inflammation resolution

Temporal control of inflammation is critical to avoid pathological developments, and is largely defined through the differential stabilities of mRNAs. While TTP-directed mRNA deadenylation is known to destabilize ARE-containing mRNAs, this mechanism alone cannot explain the variety of mRNA expression kinetics observed during inflammation resolution. Here we show that inflammation resolution requires CPEB4 expression, in vitro and in vivo. Our results identify that CPEB4-directed polyadenylation and TTP-mediated deadenylation compete during the resolutive phase of the LPS response to uncouple the degradation of pro-inflammatory mRNAs from the sustained expression of anti-inflammatory mRNAs. The outcome of this equilibrium is quantitatively defined by the relative number of CPEs and AREs in each mRNA, and further shaped by the coordinated regulation by the MAPK signalling pathway of the levels and activities of their trans-acting factors, CPEB4 and TTP. Altogether, we describe a temporal- and transcript-specific regulatory network controlling the extent of the inflammatory response.

molecular biology↗