Biology subjects

Salles, G.

Publications and source records attributed to Salles, G..

3 recordsLinked to original sources

bioRxiv2026

Relapse-founding cancer persister cells in follicular lymphoma

Follicular lymphoma (FL) is an incurable, prototypical relapse-remitting cancer, implying the existence of therapy-persistent cells that survive frontline treatment and seed disease recurrence1-3. However, these persister cells remain difficult to study directly in patients because immediate post-treatment sampling is ethically and practically challenging. Using a genetically defined mouse model that allows sampling of persistent cells immediately after frontline R-CHOP therapy, we prospectively isolate and functionally define relapse-founding cancer persister cells (CPC). The CPC is an IgM memory-like B-cell with high germinal center re-entry capacity. This state represents a discrete component of a heterogeneous residual pool indicating that residual disease is polytypic and that relapse potential may depend on which cells persist rather than on residual tumour burden alone. By integrating mouse CPC with human FL datasets, we show that an analogous transcriptional programme is detectable at diagnosis and is enriched in patients with inferior clinical outcome across independent cohorts4,5. These findings support the concept that relapse risk is linked to a conserved, genotype-agnostic CPC programme present before therapy. To explore therapeutic vulnerabilities, we developed a scalable in-vitro platform that models the CPC-like state and used it to identify sensitivity to histone deacetylase inhibition. Romidepsin and panobinostat killed CPC-like cells in-vitro, and decreased therapy-persistent cells after R-CHOP treatment in-vivo and in patient-derived organoids. Together, these data define a tractable CPC state in FL, with a validated clinical readout and an immediately testable therapeutic entry point, opening CPC-directed strategies for durable FL control.

cancer biology↗

bioRxiv2023

Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos

BackgroundFollicular lymphoma (FL) is an incurable B-cell malignancy that constitutes a quarter of all lymphomas. Although RCHOP immuno-chemotherapy induces high rates of complete remission, almost all FL patients experience multiple relapses post-treatment. The limited understanding of treatment response heterogeneity is due to the absence of in vitro or in vivo experimental models, primarily because tumor cells heavily rely on their microenvironment to survive. In this study, we present an innovative xenograft model of primary FL cells in avian embryos, circumventing these limitations. MethodsWe developed the FL-AVI-PDX model by transplanting 20 biopsy FL samples, including good (n=11) and poor clinical responders (POD24, n=9), into chicken embryos. Each set of embryos was treated with RCHOP or vehicle intravenously. We evaluated the effect of immuno-chemotherapy on tumor volume by light sheet microscopy and on tumor biology by transcriptomic analysis at the single-cell level. ResultsWe successfully engrafted all samples in avian embryos. We found that RCHOP treatment in ovo led to tumor volume reduction, which predicted progression-free survival in multivariate analysis, demonstrating the models capacity to capture clinical heterogeneity at the patient level. The FL-AVI-PDX model also provided a unique opportunity to analyze the transcriptomic impact of RCHOP on FL cells using single-cell RNA sequencing. We identified a signature of 21 genes upregulated after RCHOP exposure, displaying significant intra-tumoral heterogeneity. As a proof of concept, we validated the functional involvement of BAX, a gene from the RCHOP-induced signature, as a critical effector of immuno- chemotherapy in vitro and in avian embryos. ConclusionsThe FL-AVI-PDX model is a platform for functional precision oncology in primary FL cells that captures both inter- and intra-patient heterogeneity of clinical response to a complex therapeutic regimen. It offers a unique opportunity to better understand FL biology, opening perspectives for the development of new drugs.

cancer biology↗

bioRxiv2020

Performances of targeted RNA-sequencing for the analysis of fusion transcripts, gene mutation and expression in haematological malignancies.

RNA sequencing holds great promise to improve the diagnostic of haematological malignancies, because this technique enables to detect fusion transcripts, to look for somatic mutations in oncogenes, and to capture transcriptomic signatures nosological entities. However, the analytical performances of targeted RNA sequencing have not been extensively described in diagnostic samples. Using a targeted panel of 1385 cancer-related genes in a series of 100 diagnosis samples and 8 controls, we detected all the already known fusion transcripts, and also discovered unknown and/or unsuspected fusion transcripts in 12 samples. Regarding the analysis of transcriptomic profiles, we show that targeted RNA sequencing is performant to discriminate acute lymphoblastic leukemia entities driven by different oncogenic translocations. Additionally, we show that 86% of the mutations identified at the DNA level are also detectable at the mRNA level, except for nonsense mutations which are subjected to mRNA decay. We conclude that targeted RNA sequencing might improve the diagnosis of haematological malignancies. Standardization of the preanalytical steps and further refinements of the panel design and of the bioinformatical pipelines will be an important step towards its use in standard diagnostic procedures.

genomics↗