Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model.

By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS-PAK1-1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA-induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS-PAK1-1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA-sequencing analysis on the engrafted tumors indicates that NVS-PAK1-1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan-keratin-positive regions and potentially elevated infiltration of CD8-positive immune cells in NVS-PAK1-1-treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC.

Airborne microplastics detected in the lungs of wild birds in Japan.

Microplastics (MPs) have been found in a wide range of animal species including humans. The detection of MPs in human lungs suggests that humans inhale airborne microplastics (AMPs). Although birds respire more efficiently than mammals and are therefore more susceptible to air pollution, little is known about their inhalation exposure to MPs. In this study, we analyzed samples isolated from the lungs of several species of wild birds in Japan by attenuated total reflection (ATR) imaging method of micro-Fourier transform infrared (µFTIR) spectroscopy to clear whether AMPs can be inhaled and accumulate within the lungs of wild birds. To isolate MPs from lung samples of rock doves (Columba livia), black kites (Milvus migrans), and barn swallows (Hirundo rustica) euthanized for pest control, digestion and density separation were performed. After each sample collected on an alumina filter was measured by ATR imaging method using µFTIR spectroscopy, the physical and chemical characteristics of the detected MPs were evaluated. Six MPs were detected in 3 of 22 lung samples. Polypropylene and polyethylene were found in rock doves and ethylene vinyl acetate was found in a barn swallow. Most MPs were fragments of 28.0-70.5 µm. Our results demonstrated that in addition to dietary sources, some wild birds are exposed to MPs by inhalation, and these MPs reach the lungs.

Meis1 plays roles in cortical development through regulation of cellular proliferative capacity in the embryonic cerebrum.

Meis1 (myeloid ecotropic insertion site 1) is known to be related to embryonic development and cancer. In this study, to analyze the function of Meis1 in neural stem cells, we crossed Meis1fl/fl (Meis1 floxed) mice with Nestin-Cre mice. The results showed that Meis1-conditional knockout mice showed cerebral cortex malformation. The mice had a significantly thinner cortex than wildtype mice. At E14.5, BrdU incorporation and Pax6-positive radial glial cells were significantly decreased in the cerebral cortex of Meis1 knockout embryos as compared with wild-type embryos, whereas Tbr2-positive intermediate progenitors and NeuN-positive differentiated neurons were not. Cell death detected by immunostaining with cleaved caspase3 antibody showed no difference in the cortex between knockout and wild-type embryos. Furthermore, knockout of Meis1 in embryo by in utero electroporation showed that cellular migration was disturbed during cortical development. Therefore, Meis1 could play important roles during cortical development through the regulation of cell proliferation and migration in the embryonic cerebral cortex.

Functional Polymorphism in Pak1-3' Untranslated Region Alters Skin Tumor Susceptibility by Alternative Polyadenylation.

We identified a functional SNP in the 3' untranslated region of Pak1 that is responsible for the skin tumor modifier of MSM 1a locus. Candidate SNPs in the 3' untranslated region of Pak1 from resistance strain MSM/Ms were introduced into susceptible strain FVB/N using CRISPR/Cas9. The 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate skin carcinogenesis experiments revealed an SNP (Pak1-3' untranslated region-6C>T: rs31627325) that strongly suppressed skin tumors. Furthermore, MBNL1 bound more strongly to FVB-allele (6C/C) and regulated the transcript length in the 3' untranslated region of Pak1 and tumorigenesis through polyadenylation. Therefore, the alternative polyadenylation of Pak1 is cis-regulated by rs31627325.