Biology subjects

Bentires-Alj, M.

Publications and source records attributed to Bentires-Alj, M..

4 recordsLinked to original sources

bioRxiv2025

Bioengineered human bone-mimetic niche compositions regulatebreast cancer cell quiescence and therapy response

Disseminated tumor cells (DTCs) in the bone are widely regarded as the cellular seeds of late metastatic relapse in estrogen receptor-positive (ER+) breast cancer (BC). However, how distinct bone compartments influence BC cell quiescence and endocrine therapy response remains unclear. Mechanistic insight has been hindered by limited access to human bone samples and by the lack of relevant human models that permit controlled manipulation of stromal compartments. Here, we developed a fully human, 3D bone-mimetic system for modular, controllable assembly of engineered osteoblastic (eON), vascularized (eVN), and vascularized osteoblastic (eVON) niche compositions. These niches were generated by perfusion culture of human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) and/or human adipose tissue-derived stromal vascular fraction (hAT-SVF) cells within porous ceramic scaffolds. The resulting tissue microenvironments were then used as a substrate for the culture of an ER+ BC cell line, expressing a mutant reporter of p27 to monitor the quiescent status. We found that the eON enhanced BC cell proliferation, whereas the eVN was enriched in quiescent BC cells positive for NR2F1, a dormancy-associated transcription factor, and located near perivascular elements. Treatment with the selective ER degrader fulvestrant reduced BC cell numbers in vascularized niches (eVN and eVON) but not in eON, despite comparable receptor degradation. In summary, we developed a modular human platform for dissecting niche-specific regulation of BC quiescence, proliferation, and endocrine therapy response. The system can be further used to investigate perivascular niche-dependent mechanisms of BC cell dormancy and to guide the development of therapeutic strategies preventing recurrence in ER+ BC patients.

bioengineering↗

bioRxiv2025

The glutamine-aspartate metabolic tradeoff between fast growth and metabolic flexibility.

Cancer cells develop unique addictions to nutrients, offering attractive opportunities for clinical intervention. However, how cancer cells orchestrate and benefit from metabolic rewiring remain fundamental open questions. Here, we developed a systematic framework to investigate nutrient dependencies and applied it to study glutamine addiction. By measuring metabolite exchange rates across 54 cancer cell lines with different levels of dependency on extracellular glutamine and in human stem cells, we discovered that a dualistic regulation of glutamate biosynthesis from glutamine or aspartate, driven by the tissue of origin, generates a tradeoff between fast growth and metabolic flexibility. Monitoring dynamic metabolic adaptation to glutamine deprivation showed that the role of glutamine as limiting substrate in purine biosynthesis is not responsible for glutamine dependency. Rather, growth arrest is mediated by glutamine as a signaling molecule. Our approach opens new opportunities to map, mechanistically investigate and pharmacologically interfere with metabolic dependencies, beyond glutamine addiction.

cancer biology↗

bioRxiv2022

Single-cell analysis reveals inter- and intratumour heterogeneity in metastatic breast cancer

Metastasis is the leading cause of cancer-related deaths of breast cancer patients. Some cancer cells in a tumour go through successive steps, referred to as the metastatic cascade, and give rise to metastases at a distant site. We know that the plasticity and heterogeneity of cancer cells play critical roles in metastasis but the precise underlying molecular mechanisms remain elusive. Here we aimed to identify molecular mechanisms of metastasis during colonization, one of the most important yet poorly understood steps of the cascade. We performed single-cell RNA-Seq (scRNA-Seq) on tumours and matched lung macrometastases of patient-derived xenografts of breast cancer. After correcting for confounding factors such as the cell cycle and the percentage of detected genes (PDG), we identified cells in three states in both tumours and metastases. Gene-set Enrichment Analysis revealed biological processes specific to proliferation and invasion in two states. Our findings suggest that these states are a balance between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions (MET) traits that results in so-called partial EMT phenotypes. Analysis of the top Differentially Expressed Genes (DEGs) between these cell states revealed a common set of partial EMT Transcriptions Factors (TFs) controlling gene expression, including ZNF750, OVOL2, TP63, TFAP2C and HEY2. Our data suggest that the TFs related to EMT delineate different cell states in tumours and metastases. The results highlight the marked interpatient heterogeneity of breast cancer but identify common features of single cells from five models of metastatic breast cancer.

cancer biology↗

bioRxiv2022

ERK3/MAPK6 dictates Cdc42/Rac1 activity and ARP2/3-dependent actin polymerization

The actin cytoskeleton is tightly controlled by RhoGTPases, actin binding proteins and nucleation-promoting factors to perform fundamental cellular functions. Here, we show that ERK3, an atypical MAPK, directly acts as a guanine nucleotide exchange factor for Cdc42 and phosphorylates the ARP3 subunit of the ARP2/3 complex at S418 to promote filopodia formation and actin polymerization, respectively. Consistently, depletion of ERK3 prevented both basal and EGF-dependent Rac1 and Cdc42 activation, maintenance of F-actin content, filopodia formation and epithelial cell migration. Further, ERK3 protein binds directly to the purified ARP2/3 complex and augments polymerization of actin in vitro. ERK3 kinase activity is required for the formation of actin-rich protrusions in mammalian cells. These findings unveil a fundamentally unique pathway employed by cells to control actin-dependent cellular functions.

cell biology↗