Biology subjects

Gavrilova, A.

Publications and source records attributed to Gavrilova, A..

3 recordsLinked to original sources

bioRxiv2025

Phenotypic Plasticity and Competition Shape Therapy Sequencing in HER2+/HER2 Breast Cancer: A Mathematical Framework

Tumour heterogeneity and phenotypic plasticity are major drivers of treatment failure in cancer, enabling rapid adaptation under therapeutic pressure. In HER2-positive (HER2+) breast cancer, tumours often contain both HER2+ and HER2-negative (HER2-) cells whose interactions complicate schedule design. We develop a compact ordinary differential equation framework for intratumoral HER2+/- dynamics that integrates phenotypic plasticity with density-dependent growth and inter-phenotype competition. Phenotype-specific therapies are incorporated through simple pharmacodynamic surrogates: Paclitaxel chemotherapy acting primarily on HER2+ cells and Notch-pathway inhibition targeting HER2- cells. We use the model to compare staggered and simultaneous treatment schedules. The results show that treatment order and relative intensity critically shape long-term tumour composition. Targeted-first schedules can exhibit competitive release, whereby subsequent aggressive chemotherapy unintentionally favours HER2- expansion. In contrast, simultaneous initiation suppresses both phenotypes more effectively and avoids strong rebound. These findings highlight the importance of ecological structure in therapy design and support simultaneous combination therapy followed by targeted maintenance.

cancer biology↗

bioRxiv2025

Auxin-inducible degradation of UNC-116 in C. elegans inhibits bidirectional dense core vesicle transport and worm locomotion on different timescales

The microtubule motor kinesin-1 is vital in neurons, with mutations being associated with neurological diseases. Deletion of the Caenorhabditis elegans kinesin-1 gene unc-116 is lethal, and viable mutants are uncoordinated. Here, we use auxin-mediated degradation to deplete UNC-116 protein at different developmental stages and monitor the effects on cargo transport and locomotion. UNC-116 is substantially degraded within 1 hour of auxin treatment, by which time bidirectional dense core vesicle (DCV) motility is affected. After 4 hours, dynein-driven DCV movement is lost and only limited plus-end-directed DCV motility remains, likely driven by kinesin-3 (UNC-104). DCV movement recovers substantially after rescue from auxin for 24 hours. There is a time-lag between loss of protein and effects on locomotion, as crawling and swimming/thrashing is unaffected until 6-14 hours on auxin. By 18-24 hours, animals are as uncoordinated as the unc-116(rh24sb79) mutant. Notably, degradation of UNC-116 in neurons alone inhibits crawling and swimming, revealing the importance of neuronal kinesin-1 for locomotion. Overall, by bypassing early developmental UNC-116 functions, we reveal that UNC-116 is essential for bidirectional DCV transport and crucial for locomotion.

cell biology↗

bioRxiv2024

The role of Kinesin-1 in neuronal dense core vesicle transport and lifespan regulation in C. elegans

Fast axonal transport is crucial for neuronal function and is driven by kinesins and cytoplasmic dynein. We investigated the role of the kinesin-1 motor complex in dense core vesicle (DCV) transport in C. elegans, using mutants in kinesin light chains (klc-1 and klc-2) and the kinesin motor subunit (unc-116) expressing an ida-1::gfp transgene that labels DCVs in the ALA neuron. A reduced-function unc-116(rf) mutation greatly impaired DCV transport in both directions. A klc-2(rf) reduced-function mutation decreased DCV velocity in both directions and reduced the frequency of body bends during swimming. In contrast, the klc-1(-) null mutation had no effect on anterograde transport or swimming ability, but surprisingly it increased the speed of retrograde DCV transport. We also determined lifespan, finding that klc-1(-) or klc-2(rf) single mutants were wild-type whereas the unc-116(rf), ida-1::gfp and unc-116(rf); ida-1::gfp strains were short-lived. Strikingly, the ida-1::gfp transgenic synergistically interact with either klc mutant to extend lifespan compared to wild-type and parental strains. Our findings suggest that kinesin-1 not only influences anterograde and retrograde DCV transport but also plays a role in regulating lifespan.

cell biology↗