Biology subjects

Berthelet, J.

Publications and source records attributed to Berthelet, J..

6 recordsLinked to original sources

bioRxiv2025

LeGO-Teknik reveals that the neurogenesis pathway is a clone-specific hallmark of brain metastasis in breast cancer

Breast cancer exhibits substantial inter- and intra-patient heterogeneity. Yet the molecular features underlying this diversity and their roles in tumour progression are not yet fully elucidated. Within a primary tumour, certain clones possess a unique capacity to metastasize to distant organs, such as the brain, and this propensity may be associated with specific gene expression profiles. To investigate this phenomenon, we developed a new optical barcoding library, LeGO-Teknik, compatible with high resolution imaging, flow cytometry, single-cell RNA sequencing and machine learning computational methods. Using this new tool, we systematically assessed the fitness and organ tropism of multiple human breast cancer clones in spontaneous metastasis assays. Linking transcriptomic profiles of individual cancer cells to their clonal identities and metastatic behaviours, we identified that clones predisposed to forming brain metastases exhibit distinct molecular signatures. Notably, individual cells from these clones showed enriched expression of neurogenesis-related genes. Using SCENIC transcription factor analysis, we found that some of these features are driven by the transcription factor SOX4. This hallmark, likely due to a process of cellular reprogramming, is a remarkable example of organ mimicry during clonal selection. Together, this work provides critical insights into brain metastasis and highlights the potential for identifying predictive biomarkers and therapeutic targets for metastatic breast cancer.

cancer biology↗

bioRxiv2025

Genetic barcoding uncovers the clonal makeup of solid and liquid biopsies

Intra-tumoral heterogeneity (ITH) is fueling tumor progression in breast cancer, as specific clones present within a tumor may have a selective advantage to colonize distant organs and escape therapy. Accurate sampling of ITH is therefore a pressing challenge in clinical oncology, to adequately predict recurrence and inform rational and personalized therapies. Here we used cellular barcoding to track the spatio-temporal composition of human breast cancer clones in six preclinical models - across two cell lines and four patient derived xenografts (PDXs). This allowed direct side-by-side quantitative comparison not only of intra-tumor clonal composition, but also of how that composition was reflected in needle biopsies and cell-free DNA (cfDNA). These analyses highlighted several clinically relevant findings. First, the use of orthogonal genetic and optical barcoding revealed that clonal diversity in the center of non-necrotic primary tumors was significantly higher compared to their periphery. Second, cfDNA barcode analysis suggested that DNA shedding in the vasculature varied largely, not only depending on necrosis and tumor burden, but also between models. Third, combining information captured in both solid and liquid biopsies can provide a more robust assessment of tumor clonal composition. Taken together, these results showcases the utility of these barcoded models to optimize the use of solid and liquid biopsies as surrogate markers of ITH.

cancer biology↗

bioRxiv2023

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Brain metastasis (BM) is a dire prognosis across cancer types. It is largely unknown why some tumors metastasize to the brain whereas others do not. We analyzed genomic and transcriptional data from clinical samples of breast cancer BM (BCBM) and found that nearly all of them carried p53-inactivating genetic alterations through mutations, copy-number loss, or both. Importantly, p53 pathway activity was already perturbed in primary tumors giving rise to BCBM, often by loss of the entire 17p chromosome-arm. This association was recapitulated across other carcinomas. Experimentally, p53 knockout was sufficient to drastically increase BCBM formation and growth in vivo, providing a causal link between p53 inactivation and brain tropism. Mechanistically, p53-deficient BC cells exhibited altered lipid metabolism, particularly increased fatty acid (FA) synthesis and uptake, which are characteristic of brain-metastasizing cancer cells. FA metabolism was further enhanced by astrocytes in a p53-dependent manner, as astrocyte-conditioned medium increased FASN, SCD1, and CD36 expression and activity, and enhanced the survival, proliferation and migration of p53-deficient cancer cells. Consequently, these cells were more sensitive than p53-competent cells to FA synthesis inhibitors, in isogenic cell cultures, in BCBM-derived spheroids, and across dozens of BC cell lines. Lastly, a significant association was observed between p53 inactivation, astrocyte infiltration, and SCD1 expression in clinical human BCBM samples. In summary, our study identifies p53 inactivation as a driver of BCBM and potentially of BM in general; suggests a p53-dependent effect of astrocytes on BC cell behavior; and reveals FA metabolism as an underlying, therapeutically-targetable molecular mechanism.

cancer biology↗

bioRxiv2023

The circulating immune cell landscape stratifies metastatic burden in breast cancer patients

Advanced breast cancers show varying degrees of metastasis; however, reliable biomarkers of metastatic disease progression remain unknown. In circulation, immune cells are the first line of defence against tumour cells. Herein, using >109,591 peripheral blood mononuclear cells from healthy individuals and breast cancer patients, we tested whether molecular traits of the circulating immune cells, probed with single-cell transcriptomics, can be used to segregate metastatic profiles. Our analyses revealed significant compositional and transcriptional differences in PBMCs of patients with restricted or high metastatic burden versus healthy subjects. The abundance of T cell and monocyte subtypes segregated cancer patients from healthy individuals, while memory and unconventional T cells were enriched in low metastatic burden disease. The cell communication axes were also found to be tightly associated with the extent of metastatic burden. Additionally, we identified a PBMC-derived metastatic gene signature capable of discerning metastatic condition from a healthy state. Our study provides unique molecular insights into the peripheral immune system operating in metastatic breast cancer, revealing potential new biomarkers of the extent of the metastatic state. Tracking such immune traits associated with metastatic spread could complement existing diagnostic tools.

cancer biology↗

bioRxiv2022

Legionella para-effectors target chromatin and promote bacterial replication

Legionella pneumophila replicates intracellularly by secreting effectors via a type IV secretion system. One of these effectors is a eukaryotic methyltransferase (RomA) that methylates K14 of histone H3 (H3K14me3) to counteract host immune responses. However, it is not known how L. pneumophila infection catalyses H3K14 methylation as this residue is usually acetylated. Here we show that L. pneumophila secretes a eukaryotic-like histone deacetylase (LphD) that specifically targets H3K14ac and works in synergy with RomA. Both effectors target host chromatin and bind the HBO1 histone acetyltransferase complex that acetylates H3K14. Full activity of RomA is dependent on the presence of LphD as H3K14 methylation levels are significantly decreased in a {Delta}lphD mutant. The dependency of these two chromatin-modifying effectors on each other is further substantiated by mutational and virulence assays revealing that the presence of only one of these two effectors impairs intracellular replication, while a double knockout ({Delta}lphD{Delta}romA) can restore intracellular replication. Uniquely, we present evidence for "para-effectors", an effector pair, that actively and coordinately modify host histones to hijack the host response. The identification of epigenetic marks modulated by pathogens opens new vistas for the development of innovative therapeutic strategies to counteract bacterial infection and strengthening host defences.

microbiology↗

bioRxiv2022

The addiction-susceptibility TaqIA/Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) controls reward and metabolism through dopamine receptor type 2 (DR2)-expressing neurons

Significant evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the Taq1A polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) near the dopamine D2 dopamine receptor (DR2) gene. Depending on race it affects 30 to 80% of the population and its homozygous expression of the A1 allele correlates with a 30 to 40% reduction of striatal DR2, a typical feature of addiction, over-eating and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior is unknown. Here we used transgenic and viral-mediated strategies to reveal the role of ANKK1 in the regulation of activity and functions of the striatum. We found that Ankk1 is preferentially enriched in striatal DR2 expressing neurons and that Ankk1 loss-of-function in dorsal and ventral striatum leads to alteration in learning, impulsive, and flexible behaviors resembling the endophenotypes described in A1 carriers. We also observed an unsuspected role of ANKK1 in striatal DR2-expressing neurons in the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with versus without the A1 allele. Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for ANKK1 in the regulation of body metabolism.

neuroscience↗