Biology subjects

Nahmias, C.

Publications and source records attributed to Nahmias, C..

3 recordsLinked to original sources

bioRxiv2026

Transcriptomic profile of MTUS1-low TNBC reveals candidate therapeutic strategies.

BackgroundTriple-negative breast cancer (TNBC) is a clinically aggressive breast cancer subtype. It is a heterogeneous disease that remains difficult to stratify and that still lacks durable and biomarker-guided therapeutic options. Low expression of the tumour suppressor MTUS1 is associated with aggressive breast cancer features, but the biological properties of MTUS1-low TNBC remain insufficiently defined. Our goal was to determine whether low MTUS1 expression defines shared proliferative and stress-adaptation mechanisms that could guide candidate therapeutic strategies and corresponding target/drug pairs in MTUS1-low TNBC. MethodsWe labelled tumours from seven public TNBC RNA-seq cohorts based on the lowest and highest MTUS1 expression tertiles. Differential gene expression was analysed using gene set enrichment analysis (GSEA) on the Hallmark pathway database to identify deregulated biological pathways between MTUS1-low TNBC tumours and their MTUS1-high counterparts. Reproducibility was examined across independent TNBC cohorts and secondarily in broader breast cancer and selected TCGA tumour cohorts. Gene essentiality scores from CRISPR-Cas9 experiments in TNBC cell-line models were correlated to MTUS1 expression in these cell lines, to propose therapeutic strategies and their corresponding candidate target/drug pairs. ResultsMTUS1-low tumours showed a reproducible pathway-level proliferation mechanism driven by the MYC oncogene and sustained by up-regulated oxidative phosphorylation, combined with stress adaptation mechanisms involving unfolded protein response (UPR), and DNA repair Hallmark gene sets. Based on CRISPR data, we propose 3 therapeutic strategies: (1) targeting MYC to reduce its transcriptional activity, (2) targeting proteins from UPR, (3) targeting DNA-repair. We also propose corresponding candidate target/drug pairs to allow experimental validation of these strategies. ConclusionsProliferation in low MTUS1 TNBC is driven by MYC and stress-adaptation mechanisms. By linking this tumour profile to CRISPR-derived dependency signals, our analysis prioritises experimentally testable target-pathway hypotheses centred on MYC, UPR/proteostasis, and DNA-repair or checkpoint control. Although the proposed therapeutic strategies and candidate targets remain to be experimentally tested, the latter finding is consistent with published work showing that ATIP3-deficient TNBC cell line models are sensitive to inhibition of the WEE1 PKMYT1 G2/M checkpoint kinases.

cancer biology↗

bioRxiv2025

Microtubule deacetylation drives kinesin-1 mediated mitochondrial transport accelerating breast cancer cell migration

Mitochondrial trafficking is reprogrammed in metastatic breast cancer cells to sustain their migratory and invasive behavior. Mitochondria repositioning to sites of high energy demand is governed by a balance between opposing dynein and kinesin-1 (KIF5B) molecular motors whose regulation remains incompletely understood. Here, we identify the SYBU gene as a candidate prognostic marker downregulated in metastatic disease. SYBU encodes syntabulin, a mitochondria outer membrane protein that interacts with dynein to counterbalance KIF5B-dependent anterograde transport to the cell cortex. Loss of SYBU disrupts the balance, causing excessive KIF5B-driven mitochondria movement, microtubule damage and deacetylation. In turn, microtubule deacetylation reinforces KIF5B-mediated transport, creating a positive feedback loop that drives mitochondria distribution close to the cell periphery and enhances cancer cell migration. Pharmacological inhibition of the tubulin deacetylase HDAC6 restores mitochondrial positioning and reduces cell migration in SYBU-deficient cells. Our findings identify SYBU as a key regulator of mitochondrial trafficking and pave the way to personalized therapeutic approaches for metastatic breast tumors with low SYBU expression.

cell biology↗

bioRxiv2023

Aneuploidy triggers vulnerability to WEE1 inhibition via severe chromosome pulverization

Aneuploidy, a hallmark of cancer, is a prominent feature associated with poor prognosis in breast cancer. Here, we screened a panel of cell cycle kinase inhibitors to identify novel targets for highly aneuploid breast cancers. We show that increasing aneuploidy in breast cancer cells sensitizes to the inhibition of WEE1 kinase. Upon exposure to WEE1 inhibitor, aneuploid cells exhibit aberrant mitosis characterized by the detachment of centromere proteins from centromeric DNA and pulverization of chromosomes. The occurrence of such phenotype is driven by excessive levels of replication stress and DNA damage during S-phase, that in turn trigger major defects in the subsequent mitosis. We show that DNA2 helicase/nuclease, that regulates replication of centromeric DNA, is the key player responsible for severe chromosome pulverization in mitosis. The heightened vulnerability of aneuploid cells to WEE1 inhibition, coupled with underlying molecular mechanisms, provides a rationale for clinical exploration of WEE1-targeted therapies against aneuploid breast cancers. Impact StatementIncreased vulnerability of aneuploid cells to WEE1 inhibition is orchestrated by the DNA2 nuclease/helicase. These findings open new therapeutic strategies in the context of personalized medicine in breast cancer.

cell biology↗