Biology subjects

Ben-Yishay, R.

Publications and source records attributed to Ben-Yishay, R..

2 recordsLinked to original sources

bioRxiv2026

Epithelial mesenchymal transition initiates precancer states in BRCA1 mutation carriers

Epithelial-to-mesenchymal transition (EMT) is activated to equip cells with the capacity to adapt to and escape hostile conditions. While EMT is required for cancer progression, its role in breast cancer initiation remains elusive. Given the basal-like phenotype of breast cancers arising in female carriers of germline BRCA1 pathogenic variants (BRCA1 carriers), we hypothesized that enhanced EMT susceptibility underlies precancerous initiation in mammary epithelium. Perturbation of patient-derived normal mammary organoids from BRCA1 carriers and non-carriers with inflammatory cytokines induced copy number variations (CNV) and the acquisition of oncogenic mutations in both groups. However, in organoids derived from BRCA1 carriers, cytokine exposure induced morphological, transcriptomic, and functional EMT, accompanied by a transition to basal-like phenotype. Concomitant DNA damage accumulation in organoids from BRCA1-carriers demonstrated PARP inhibitor sensitivity. EMT-primed states were identified in a subpopulation of normal mammary epithelium from BRCA1 carriers. We demonstrate the utility of patient-derived normal BRCA1 heterozygous mammary organoids to reveal a plastic, high-risk epithelial state that is associated with a transient, targetable vulnerability.

cancer biology↗

bioRxiv2026

Asymmetric crosstalk between the BMP and TGFβ pathways resolves signaling ambiguity

The BMP and TGF{beta} signaling pathways control cellular fate decisions in diverse biological contexts, often playing opposing roles. Despite extensive knowledge of these pathways, understanding how cells respond to environments containing these opposing cues remains a challenge. Here, we systematically analyze the activation of these pathways under combinatorial signaling environments. We find that TGF{beta} ligands inhibit BMP signaling, while BMP ligands enhance TGF{beta} transcriptional response across concentrations, ligand variants, and cell types. This asymmetric crosstalk results in the activation of a TGF{beta}-biased transcriptional response, even under mixed signaling conditions, effectively reducing signal ambiguity, with implications for processes such as EMT. We show that this crosstalk originates downstream of the SMAD proteins phosphorylation. Using mathematical models, we predict, and experimentally verify, that promiscuous interactions between SMAD proteins provide the mechanism for the observed crosstalk. Our findings challenge the canonical models, suggesting an active role for mediator proteins in determining biological responses.

systems biology↗