Biology subjects

Pommier, R.

Publications and source records attributed to Pommier, R..

3 recordsLinked to original sources

bioRxiv2025

The epigenetic regulator TRIM24 controls melanoma cell dedifferentiation and resistance to treatment in melanoma

Cancer cell plasticity plays a key role in tumor progression and treatment resistance in melanoma. While the transcriptional programs enabling adaptative switching between melanocytic and mesenchymal phenotypes are well characterized, unravelling druggable epigenetic regulators that sustain melanoma cell adaptation and resistance remains crucial. Herein, we identified TRIM24, a bromodomain protein frequently upregulated during melanoma metastatic progression, as a crucial regulator of melanoma cell plasticity towards invasive/resistant states. shRNA-mediated knock-down of TRIM24 or degradation using a TRIM24-specific PROTAC decrease the migratory capacities and increase the sensitivity to BRAF inhibitors of melanoma cells. Integration of transcriptomic (RNA-seq) and epigenomic (ATAC-seq, CUT&Tag) analyses reveals that TRIM24 reprograms the epigenome of melanoma cells, promoting mesenchymal and repressing melanocytic transcriptional programs. We further define a TRIM24-specific transcriptional signature, that is consistently enriched in treatment-resistant mesenchymal subpopulations in melanoma single-cell RNA-seq datasets. Accordingly, analysis of TRIM24 protein expression in melanoma patients highlights that high TRIM24 expression correlates with relapse to adjuvant immunotherapy. Finally, TRIM24 knock-down in immunocompetent mouse models synergises with immune checkpoint inhibitors. Overall, our findings spotlight TRIM24 as a major epigenetic regulator driving melanoma cell dedifferentiation and resistance to therapy, representing a promising druggable target to reverse phenotype switching and resensitize to treatment.

cancer biology↗

bioRxiv2025

Oncogenic Stress is a Novel Immunogenic Signal Driven by the Unfolded Protein Response and Detected by Neutrophils

Breast cancer (BC) is the leading cause of cancer-related death in women. However, early detection of BC remains a major clinical challenge and represents a significant obstacle to effective prevention. To improve early clinical management, a deeper understanding of the preneoplastic immune microenvironment of BC is crucial. Among innate immune populations, neutrophils have emerged as important modulators of tumor development, but their role during the initiation of BC remains poorly understood. By integrating depletion experiments with transcriptomic profiling of sorted preneoplatic epithelial cells and neutrophils in spontaneous breast cancer mouse models, we observed that neutrophils contribute to tumor surveillance of preneoplastic stage with the activation of the unfolded protein response (UPR) in the preneoplastic epithelial compartment. To decipher the early anti-tumoral role of neutrophil, we developed an in vitro co-culture model of human mammary epithelial cells undergoing oncogenic stress with activation of the UPR (eHMEC), with human primary neutrophils. eHMEC display an immunoactive secretome as well as immunogenic membrane ligands, and neutrophils are the only immune cell population detecting eHMEC immunogenic signals leading to their recruitment, activation, production of reactive oxygen species and degranulation. Altogether, our work identifies for the first-time neutrophils as the earliest immune cell involved in immunosurveillance of preneoplastic BC epithelial cells, paving the way for potential therapeutic approaches targeting neutrophils to intercept early steps of BC tumorigenesis.

immunology↗

bioRxiv2023

Spatial transcriptomics reveal pitfalls and opportunities for the detection of rare high-plasticity breast cancer subtypes

Breast cancer is one of the most prominent types of cancers, in which therapeutic resistance is still a major clinical hurdle. Specific subtypes like Claudin-low (CL) and metaplastic breast cancers (MpBC) have been associated with high non-genetic plasticity, which can facilitate resistance. The overlaps and differences between these orthogonal subtypes, respectively identified by molecular and histopathological analyses, are however still insufficiently characterised. Adequate methods to identify high-plasticity tumours to better anticipate resistance are furthermore still lacking. Here we analysed 11 triple negative breast tumours, including 3 CL and 4 MpBC samples, via high-resolution spatial transcriptomics. We combined pathological annotations and deconvolution approaches to precisely identify tumour spots, on which we performed signature enrichment, differential expression and copy-number analyses. We used the TCGA and CCLE public databases for external validation of expression markers. By levying spatial transcriptomics to focus analyses only to tumour cells in MpBC samples, and therefore bypassing the negative impact of stromal contamination, we could identify specific markers that are not expressed in other subtypes nor stromal cells. Three markers (BMPER, POPDC3 and SH3RF3) could furthermore be validated in external expression databases encompassing bulk tumour material and stroma-free cell lines. We find that existing bulk expression signatures of high-plasticity breast cancers are relevant in mesenchymal transdifferentiated compartments but can be hindered by stromal cell prevalence in tumour samples, negatively impacting their clinical applicability. Spatial transcriptomics analyses can however help identify more specific expression markers, and could thus enhance diagnosis and clinical care of rare high-plasticity breast cancers.

cancer biology↗