Biology subjects

Lamballe, F.

Publications and source records attributed to Lamballe, F..

3 recordsLinked to original sources

bioRxiv2026

The atypical cadherin CELSR2 regulates distinct epithelial-mesenchymal states and oxidative phosphorylation in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by marked intratumoral heterogeneity, which contributes to metastatic dissemination, therapeutic resistance, and poor clinical outcome. Epithelial-mesenchymal plasticity is a major contributor to this heterogeneity. Identifying the molecular regulators governing epithelial-mesenchymal plasticity is therefore essential to understanding how distinct tumor cell populations arise and fuel TNBC progression. Here, we identify the adhesion G protein-coupled receptor CELSR2 as an independent poor-prognosis marker and regulator of epithelial-mesenchymal plasticity in TNBC. Spatial transcriptomic analyses revealed segregation of CELSR2high tumor cells within the epithelial tumor core and CELSR2low tumor cells at the invasive front. In line with the latter observation, CELSR2 expression decreases during EMT and its loss promotes acquisition of a hybrid epithelial-mesenchymal state. CELSR2high tumor cells display a CREB-associated oxidative phosphorylation (OXPHOS) program and promote cell proliferation and primary tumor growth. Conversely, CELSR2low cells display features of a more migratory phenotype. Collectively, our findings identify CELSR2 as a previously unknown regulator of epithelial-mesenchymal plasticity and reveal that heterogeneous CELSR2 expression shapes spatially and functionally distinct tumor cell populations, thereby contributing to intratumoral heterogeneity in TNBC.

cancer biology↗

bioRxiv2021

BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

Cell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments. MethodsBioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. The MMTV-R26Met mouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drugs mechanisms of action. ResultsWe report that high expression levels of BCL-XL and specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to all MMTV-R26Met and human TNBC cell lines tested. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell growth by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis. ConclusionsOur studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.

cancer biology↗

bioRxiv2020

Modeling heterogeneity of Triple-Negative Breast Cancer highlights potency of WEE1 and BCL-XL targeting

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, we generated a unique mouse model (MMTV-R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor. MMTV-R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26Met tumors and machine learning approach showed that the model faithfully recapitulates inter-tumoral heterogeneity of human TNBC. Further signaling network analysis highlighted potential druggable targets, of which co-targeting of WEE1 and BCL-XL synergistically killed TNBC cells and efficiently induced tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe and apoptosis. Our study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.

cancer biology↗