Tomasso, M. R. | bioRxiv Science

bioRxiv2022

A first-in-class Wiskott-Aldrich syndrome protein (WASp) activator with anti-tumor activity in hematological cancers

Hematological cancers are among the most common cancers in adults and in children. Despite significant improvements in therapies, many patients still succumb to the disease, therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family proteins regulate actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations, auto-inhibited and active conformations. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as single agent in lymphoma, leukemia and multiple myeloma, including models of secondary resistance to PI3K, BTK and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization induced by EG-011 was demonstrated with multiple techniques. Transcriptome analysis highlighted homology with drugs inducing actin polymerization. Key pointsO_LIEG-011 is a novel small molecule with anti-tumor activity in hematological cancers, including resistant lymphoma and multiple myeloma models C_LIO_LIEG-011 is a first-in-class small molecule activator of the auto-inhibited form of the Wiskott-Aldrich syndrome protein (WASp) C_LI

cancer biology↗

bioRxiv2022

Septins mediate a microtubule-actin crosstalk that enables actin growth on microtubules

Cellular morphogenesis and processes such as cell division and migration require the coordination of the microtubule and actin cytoskeletons (1, 2). Microtubule-actin crosstalk is poorly understood and largely regarded as the capture and regulation of microtubules by actin (1, 2). Septins are filamentous GTP-binding proteins, which comprise the fourth component of the cytoskeleton along microtubules, actin and intermediate filaments (3, 4). Here, we report that septins mediate microtubule-actin crosstalk by coupling actin polymerization to microtubule lattices. Super-resolution imaging shows that septins localize to overlapping microtubules and actin filaments in the growth cones of neurons and non-neuronal cells. We show that recombinant septin complexes directly crosslink microtubules and actin filaments into hybrid bundles. In vitro reconstitution assays reveal that microtubule-bound septins capture and align stable actin filaments with microtubules. Strikingly, septins enable the capture and polymerization of growing actin filaments on microtubule lattices. In neuronal growth cones, septins are required for the maintenance of the peripheral actin network that fans out from microtubules. These findings provide the first evidence of septins directly mediating microtubule interactions with actin filaments, and reveal a new mechanism of microtubule-templated actin growth with broader significance for the self-organization of the cytoskeleton and cellular morphogenesis. Significance StatementCellular morphogenesis and processes such as cell division and cell migration require the coordination of the actin and microtubule cytoskeletons. Despite its broader physiological significance, actin-microtubule crosstalk is molecularly and mechanistically poorly understood. Actin-microtubule crosstalk has been viewed primarily as the regulation or guidance of microtubule dynamics by actin filaments. Here, we have discovered a new mechanism by which actin filament growth is guided by microtubules. We report that septins, a poorly understood component of the cytoskeleton, can capture and link the polymerizing ends of actin filaments to microtubule polymers. We present evidence that this new septin-mediated mechanism is critical for the morphology of growth cones, which are structures that direct the growth of neuronal axons through actin-microtubule crosstalk.

cell biology↗