Uribe-Alvarez, C. | bioRxiv Science

bioRxiv2019

Targeting effector pathways in RAC1P29S-driven malignant melanoma

Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recently, genomic analyses revealed that 4-9% of sun-exposed melanoma bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signaling from RAC1P29S, we here extend this analysis to examine the roles of PI3Ks and SRF/MITF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036) and certain PI3Ks inhibitors (BKM120, TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not mutant BRAF, however other PI3K inhibitors, including PI3K-selective inhibitors are less effective. Similar results were seen in vivo, using embryonic zebrafish development as a readout, but now including an SRF/MRTF inhibitor (CCG-203971). These results suggest that targeting Group A PAKs and/or SRF/MRTF represent promising approach to suppress RAC1 signaling in malignant melanoma.

cancer biology↗

bioRxiv2019

Staphylococcus epidermidis metabolic adaptation and biofilm formation in response to varying oxygen.

Staphylococcus epidermidis is a Gram-positive saprophytic bacterium found in the microaerobic/anaerobic layers of the skin. It becomes a health hazard when introduced across the skin by punctures or wounds. S. epidermidis forms biofilms in low O2 environments. As oxygen concentrations ([O2]) decreased, the metabolism of S. epidermidis was modified ranging from fully aerobic to anaerobic. Respiratory activity increased at high [O2], while anaerobically grown cells exhibited the highest rate of fermentation. High aerobic metabolism coincided with high hydrogen peroxide-mediated damage. Remarkably, the rate of growth decreased at low [O2] even though the concentration of ATP was high. Under these conditions bacteria associated into biofilms. Then, in the presence of metabolic inhibitors, biofilm formation decreased. It is suggested that when [O2] is low S. epidermidis accumulates ATP in order to synthesize the proteins and polysaccharides needed to attach to surfaces and form biofilms.\n\nImportanceBacteria and humans coexist, establishing all kinds of relationships that may change from saprophytic to infectious as environmental conditions vary. S. epidermidis is saprophytic when living in the skin. Inside the organism it evokes a pathologic reaction and is thus rejected by the organism. Additionally it is forced to adapt to high oxygen concentrations, becoming vulnerable to reactive oxygen species, which may come from leukocyte attack. Avoiding both, high oxygen and leukocytes is a must for bacteria. Escaping from oxygen involves a clever response: whenever it finds a low oxygen environment it attaches to surfaces, associating into biofilms. Biofilms protect S. epidermidis against host cells. Understanding these responses is a must in order to develop treatments and prevent infection success.

physiology↗