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The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl + cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.

The Jurassic relict Royal fern, Osmunda regalis L., is widely distributed across temperate zones in the Northern and Southern hemispheres. Even though this species has been utilised for centuries as a medicinal plant, its phytochemical composition mainly remains unknown. As part of our ongoing research to identify potential lead compounds for future anticancer drugs, 17 natural products were characterised from the aerial parts of Osmunda regalis L. Fifteen of these compounds were identified in this species for the first time, including the six previously undescribed compounds kaempferol 3-O-(2"-O-(2"'-α-rhamnopyranosyl)-β-glucopyranosyl)-β-glucopyranoside, quercetin 3-O-(2"-O-(2"'-α-rhamnopyranosyl)-β-glucopyranosyl)-β-glucopyranoside, kaempferol 3-O-(2"-O-(2"'-α-rhamnopyranosyl-6"'-O-(E)-caffeoyl-)-β-glucopyranosyl)-β-glucopyranoside, 3-methoxy-5-hydroxy-4-olide, 4-hydroxy-3-(3'-hydroxy-4'-(hydroxyethyl)-oxotetrafuranone-5-methyl tetrahydropyranone, and 4-O-(5-hydroxy-4-oxohexanoyl) osmundalactone. The molecular structures were determined by combining several 1D and 2D NMR experiments, circular dichroism spectroscopy, and HRMS. Determination of cytotoxicity against AML MOLM-13, H9c2, and NRK cell lines showed that two isolated lactones exhibited significant cytotoxic activity. [ABSTRACT FROM AUTHOR]

Harvested Laminaria hyperborea contributes to approximately 3.3 million tonnes of epiphytes discarded as waste despite containing organisms such as red algae and bryozoa, known to produce a range of high-value and bioactive compounds. Our research aim is to valorize epiphyte biomass by exploring the cytotoxic and antimicrobial potential in various extracts and optimized fractionation by flash chromatography. All extracts and fractions were tested for cytotoxicity towards cell lines derived from Acute Myeloid Leukemia (AML), prostate cancer (PC-3), and breast cancer (MCF-7), as well as non-tumorigenic cell lines from the kidney and heart using metabolic activity as a read-out. Antimicrobial activitywas assessed using microplate based Alamar Blue assay and minimum inhibitory concentration (MIC) to determine the MIC against various human pathogens. Six extracts demonstrated significant cytotoxicity across all five cell lines (EC50 values below 46 μg/mL), while hexane extract selectively targeted AML cells with EC50 of 1.1 μg/mL. The hexane and ethyl acetate extracts displayed antimycobacterial and antifungal activity (MIC 100 μg/mL). Amultistep flash fractionation of themethanolic extract revealed several cytotoxic and antimicrobial activities. The flash fractions displayed a selective activity pattern depending on the elution solvent. Nine fractions were cytotoxic towards all cell lines (EC50 below 72 μg/mL), and four were highly cytotoxic (EC50 below 5.4 μg/mL). Two non-polar fractions were selective for the AML cell line. These results highlight the potential for discovering anticancer and antimicrobial compounds in epiphytes from Laminaria, necessitating further research on their active compounds. Overall, this work underscores the environmental and scientific value of converting marine by-products into a valuable resource, aligning with sustainability and ethical goals. [ABSTRACT FROM AUTHOR]