The major microtubule-organizing center (MTOC) in animal cells, the centrosome, comprises a pair of centrioles surrounded by pericentriolar material (PCM), which nucleates and anchors microtubules. Centrosome assembly depends on PCM binding to centrioles, PCM self-association and dynein-mediated PCM transport, but the self-assembly properties of PCM components in interphase cells are poorly understood. Here, we used experiments and modeling to study centriole-independent features of interphase PCM assembly. We showed that when centrioles are lost due to PLK4 depletion or inhibition, dynein-based transport and self-clustering of PCM proteins are sufficient to form a single compact MTOC, which generates a dense radial microtubule array. Interphase self-assembly of PCM components depends on γ-tubulin, pericentrin, CDK5RAP2 and ninein, but not NEDD1, CEP152 or CEP192. Formation of a compact acentriolar MTOC is inhibited by AKAP450-dependent PCM recruitment to the Golgi or by randomly organized CAMSAP2-stabilized microtubules, which keep PCM mobile and prevent its coalescence. Linking of CAMSAP2 to a minus-end-directed motor leads to the formation of an MTOC, but MTOC compaction requires cooperation with pericentrin-containing self-clustering PCM. Our data reveal that interphase PCM contains a set of components that can self-assemble into a compact structure and organize microtubules, but PCM self-organization is sensitive to motor- and microtubule-based rearrangement.

Despite clinical successes in the treatment of some early stage cancers, it is undeniable that novel and innovative approaches are needed to aid in the fight against cancer. Targeted therapies offer the desirable feature of tumor specificity while sparing healthy tissues, thereby minimizing side effects. However, the success rate of translation of these therapies from the preclinical setting to the clinic is dramatically low, highlighting an important point of necessary improvement in the drug development process in the oncology field. The practice of a comparative oncology approach can address some of the current issues, by introducing companion animals with spontaneous tumors in the linear drug development programs. In this way, animals from the veterinary clinic get access to novel/innovative therapies, otherwise inaccessible, while generating robust data to aid therapy refinement and increase translational success. In this review, we present an overview of targetable membrane proteins expressed in the most well-characterized canine and feline solid cancers, greatly resembling the counterpart human malignancies. We identified particular areas in which a closer collaboration between the human and veterinary clinic would benefit both human and veterinary patients. Considerations and challenges to implement comparative oncology in the development of anticancer targeted therapies are also discussed.

The major microtubule-organizing center (MTOC) in animal cells, the centrosome, comprises a pair of centrioles surrounded by pericentriolar material (PCM), which nucleates and anchors microtubules. Centrosome assembly depends on the interactions of PCM with centrioles, PCM self-association and dynein-mediated transport. Here, we show that if centrioles are lost due to PLK4 depletion or inhibition, PCM still forms a single centrally located MTOC when non-centrosomal microtubule minus end organization pathways are disabled. Acentriolar MTOC assembly depends on dynein-driven coalescence of PCM clusters with attached microtubule minus ends and requires γ-tubulin, pericentrin, CDK5RAP2 and ninein, but not NEDD1, CEP152 or CEP192. PCM self-assembly is inhibited by AKAP450-dependent PCM recruitment to the Golgi and by CAMSAP2-mediated microtubule minus end stabilization. However, if CAMSAP2 is linked to a minus-end-directed motor, a single MTOC containing PCM components can still form, and its organization depends on the presence of pericentrin. Our results reveal that the formation of a single central MTOC in interphase mammalian cells is not strictly centriole dependent but can be driven by self-organization of PCM and microtubule minus ends.

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