Biology subjects

Norton, K.

Publications and source records attributed to Norton, K..

2 recordsLinked to original sources

bioRxiv2026

Metabolic-epigenetic coupling between leucine catabolism and glycolysis drives CDK4/6 inhibitor resistance

Resistance to CDK4/6 inhibitors limits the durability of therapy for ER+ breast cancer. Despite the identification of mechanisms that regulate resistance, the metabolic adaptations that enable therapeutic escape remain poorly understood. Here, we identify a metabolic-epigenetic circuit that drives resistance by coordinately rewiring amino acid and glucose metabolism. CDK4/6 inhibitor-resistant ER+ tumor cells upregulate the leucine transporter SLC7A5, enhancing leucine uptake. SLC7A5 overexpression is sufficient to confer palbociclib resistance across ER+ cell lines, patient-derived organoids and xenografts. Stable isotope tracing in cell lines and in xenograft tumors revealed that leucine is catabolized through BCAT2 and HMGCL to increase acetyl-CoA levels, and elevated acetyl-CoA promotes H3K27 acetylation at the GLUT1 promoter, upregulating GLUT1 expression and glycolytic activity. Disrupting leucine transport, catabolism, or availability suppresses GLUT1 expression and restores therapeutic sensitivity in resistant models. In patients receiving palbociclib-based therapy, high SLC7A5 expression and coordinated SLC7A5-GLUT1 co-expression are associated with shorter progression-free survival. Together, these findings define a metabolic-epigenetic mechanism linking branched-chain amino acid catabolism to glycolysis and identify a biomarker-associated metabolic vulnerability in advanced ER+ breast cancer.

cancer biology↗

bioRxiv2026

Cheetahs Combine Head Pitch Stabilisation with Predictive Yaw Tracking during High-speed Pursuit

Predators pursuing agile prey must coordinate locomotion with rapidly changing visual information, yet how they control head orientation during high-speed terrestrial pursuit remains poorly understood. We reconstructed three-dimensional head, torso, and lure target trajectories from synchronised multi-camera recordings of freely running cheetahs (Acinonyx jubatus) using model-based markerless reconstruction, and propagated reconstruction uncertainty through Monte Carlo analysis. Across 1,373 valid reconstructed pursuit frames, head pitch was more closely aligned with the target than torso pitch, and is tightly stabilised relative to target elevation. Head-on-torso counter-rotation nearly cancelled concurrent torso-pitch rotations, preserving target-relative head pitch despite locomotor oscillations. In yaw, cheetahs predominantly oriented their heads ahead of the target's instantaneous position while maintaining a distinct locomotor heading and continuing to close range. During steady-lateral pursuit, head yaw was best described by a short horizon constant-velocity extrapolation model with a cross-validated median prediction horizon of 45 ms. Together, these findings reveal complementary head orientation strategies during pursuit: robust sagittal stabilisation and predictive lateral tracking keep the head target-referenced while the torso generates a closing trajectory towards intersection.

animal behavior and cognition↗