Biology subjects

Evason, K.

Publications and source records attributed to Evason, K..

3 recordsLinked to original sources

bioRxiv2026

Multi-Modal Kinome Profiling Discovers Mesenchymal-Like Polarity Networks that Underly Directed Hepatocellular Carcinoma Cell Migration

Metastasis and associated therapy resistance remain the principal drivers of cancer related death, and there is a pressing need for a deeper mechanistic understanding and anti-metastatic therapies. For patients that suffer from hepatocellular carcinomas (HCCs), which are the most common primary liver cancers, frequent systemic metastasis results in bleak 5-year survival prognoses of only 4%. To metastasize, carcinoma cells must acquire an invasive phenotype, which typically requires switching from an epithelial-like apical-basal polarity to the front-rear polarity of mesenchymal-like cells. Signaling cues that originate in the tumor microenvironment can activate cellular morphogenic programs that drive polarity switching, like the epithelial-mesenchymal transition (EMT). Protein kinases control most cell signaling pathways and are highly actionable drug targets; however, systematic studies determining the kinases that underly the epithelial-mesenchymal polarity switch (EMPS) are lacking. We developed an assay platform that integrates mass spectrometry (MS)-based kinome profiling, broadly capturing kinase network activity, with chemical genetic screening using selective kinase inhibitors and quantitative phase imaging (QPI), serving as the phenotypic readout. Applying this approach that we dubbed morphokin-MS, to epithelial-like HCC cell lines that we induced to undergo EMPS identified a conserved network of 12 kinases that contributed to HCC cell polarity switching and directed cell migration; MS-based kinome profiling of 17 HCC patient tumors showed that these kinase are frequently upregulated in human tumors. morphokin-MS also revealed that death-associated protein kinase 3 (DAPK3) is one of the principal drivers of the EMPS and directed HCC cell migration. Thus, our mechanistic studies revealed that DAPK3 forms a complex with DAPK1 and filamin-A inter-acting protein 1-like (FILIP1L), which act as scaffold proteins that recruit DAPK3 to the centrosome. Pharmaco-logical and genetic inhibition of the DAPK1-DAPK3-FILIP1L complex blocked centrosome repositioning and microtubule polarization toward the leading edge of mesenchymal-like HCC cells, directed cell migration, and invasion. Our morphokin-MS method and comprehensive kinome profiling data will serve as a valuable resource for the cancer research community; our discovery of an inducible mesenchymal-like DAPK1-DAPK3-FILIP1L polarity complex that controls centrosome positioning in motile HCC cells may lead to the development of novel therapeutics for combatting cancer metastasis.

cancer biology↗

bioRxiv2025

EPHB2 promotes diet-induced MASH liver fibrosis

The EphB2 receptor tyrosine kinase is thought to participate in numerous fibroinflammatory disorders. In metabolic dysfunction-associated steatohepatitis (MASH), we find EphB2 becomes strongly overexpressed and overactive in hepatic stellate cells (HSCs) from humans with the disease and from mice fed liver-injuring high fat diets. Genetic deletion of EphB2 or inactivation of its tyrosine kinase catalytic domain suppressed diet-induced MASH fibrosis, while a kinase overactive point mutant displayed exacerbated steatosis and hepatic damage. Silencing EphB2 in primary HSCs dampened the ability of TGF-{beta}/SMAD signals to stimulate the transdifferentiation of stellate cells into profibrotic myofibroblasts, and HSC-specific deletion of the receptor, but not hepatocyte deletion, reduced liver scarring in multiple mouse models, even after fibrosis was established. Finally, a newly developed small molecule tetramerization inhibitor that targets EphB2-Ephrin receptor-ligand interactions effectively blunts inflammation and fibrosis in chemical and diet-induced liver injury models, demonstrating that therapeutically targeting EphB2 can counter MASH fibrosis.

pathology↗

bioRxiv2023

Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma

Background and AimsActivating mutations in the CTNNB1 gene encoding {beta}-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). HCC with CTNNB1 mutations show profound alterations in lipid metabolism including increases in fatty acid oxidation and transformation of the phospholipidome, but it is unclear how these changes arise and whether they contribute to the oncogenic program in HCC. MethodsWe employed untargeted lipidomics and targeted isotope tracing to quantify phospholipid production fluxes in an inducible human liver cell line expressing mutant {beta}-catenin, as well as in transgenic zebrafish with activated {beta}-catenin-driven HCC. ResultsIn both models, activated {beta}-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid flux analysis in human cells revealed a large reduction in phosphatidylcholine (PC) production rates as assayed by choline tracer incorporation. We developed isotope tracing lipid flux analysis for zebrafish and observed similar reductions in phosphatidylcholine synthesis flux accomplished by sex-specific mechanisms. ConclusionsThe integration of isotope tracing with lipid abundances highlights specific lipid class transformations downstream of {beta}-catenin signaling in HCC and suggests future HCC-specific lipid metabolic targets. SynopsisIn this work, we show by lipid specific isotope tracing that mutations in the oncogene CTNNB1 leads to conserved changes in lipid metabolism in hepatocellular carcinoma. These include the stimulation of fatty acid oxidation and a suppression of phosphorylcholine synthesis.

cancer biology↗