Verdi, V. | Search bioRxiv

bioRxiv2026

Orthogonal cell division organizes surface virulence factors to drive staphylococcal abscess community formation

During infection, Staphylococcus aureus forms dense multicellular structures, called staphylococcal abscess communities (SACs), that are encased in a capsule made of host fibrin to evade host immune defenses. S. aureus cells divide characteristically along successive orthogonal planes, but the contribution of this division geometry to infection is unclear. Here, we show that disrupting orthogonal cell division by deleting the cell division septum placement factor PcdA impairs SAC formation in vivo and in a three-dimensional in vitro model. Loss of PcdA leads to uneven surface distribution of adhesins containing the YSIRK signal sequence that directs their insertion into the division septum, thereby resulting in uneven interaction with fibrin fibers. Consequently, bacterial communities fail to establish a robust fibrin pseudocapsule and remain accessible to immune cells. We propose that orthogonal cell division coordinates cell cycle progression with extracellular matrix engagement, SAC architecture, and persistence within host tissues. HIGHLIGHTSO_LIOrthogonal cell division promotes staphylococcal abscess community formation C_LIO_LILoss of PcdA disrupts fibrin pseudocapsule assembly in 3D models C_LIO_LIDivision geometry ensures uniform surface deployment of adhesins C_LIO_LICell division plane selection links bacterial cell cycle control to virulence C_LI

microbiology↗

bioRxiv2025

Capacity for compensatory cyclin D2 response confers trametinib resistance in canine mucosal melanoma

Background/objectiveMucosal melanoma (MM) is a poorly responsive, rare and aggressive subtype with paucity of targetable recurrent driver mutations, although Ras/MAPK and PI3K/AKT/mTOR signaling pathway activations are common. Eventual tumor evasion of targeted therapy continues to limit treatment success. Adequate models are necessary to address therapeutic resistance. The relatively greater incidence of naturally occurring MM in dogs, as well as its comparable clinical and pathological characteristics to human MM, represents a promising opportunity for predictive patient modeling. Resistance-promoting crosstalk between Ras/MAPK and PI3K/AKT/mTOR signaling under trametinib inhibition of MEK was studied in a canine MM model. Emphasis was placed on the suppressive effect of trametinib on cell cycle entry and its potential role in drug resistance. MethodsD-type cyclins were investigated using five MM cell lines exhibiting differential sensitivities to trametinib. Drug-treated cells were analyzed for signaling pathway activation, proliferation, survival, cell death, and cell cycle in the context of D-type cyclin expression. Cyclin D2 expression was manipulated using siRNA knock down or inducible recombinant overexpression. ResultsWith diminished cyclin D1 under trametinib treatment, relatively trametinib-resistant MM cells exhibited capacity to upregulate cyclin D2, which promoted proliferation, whereas sensitive cells did not similarly respond. Inhibition of the compensatory cyclin D2 response restored sensitivity to resistant cells. Induced cyclin D2 overexpression promoted survival to otherwise trametinib-sensitive MM cells that did not exhibit capacity to upregulate endogenous cyclin D2. PI3K/AKT/mTOR signaling upregulation under trametinib was suppressed by mTORC1/2 inhibition, which similarly diminished cyclin D2 response. ConclusionThe compensatory switch from preferential reliance on cyclin D1 to D2 appears to play a role in MM resistance to MEK inhibition.

cancer biology↗