Phase separation of SHP2E76K promotes malignant transformation of mesenchymal stem cells by activating mitochondrial complexes.

Mesenchymal stem cells (MSCs), suffering from diverse gene hits, undergo malignant transformation and aberrant osteochondral differentiation. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a nonreceptor protein tyrosine phosphatase, regulates multicellular differentiation, proliferation, and transformation. However, the role of SHP2 in MSC fate determination remains unclear. Here, we showed that MSCs bearing the activating SHP2E76K mutation underwent malignant transformation into sarcoma stem-like cells. We revealed that the SHP2E76K mutation in mouse MSCs led to hyperactive mitochondrial metabolism by activating mitochondrial complexes I and III. Inhibition of complexes I and III prevented hyperactive mitochondrial metabolism and malignant transformation of SHP2E76K MSCs. Mechanistically, we verified that SHP2 underwent liquid-liquid phase separation (LLPS) in SHP2E76K MSCs. SHP2 LLPS led to its dissociation from complexes I and III, causing their hyperactivation. Blockade of SHP2 LLPS by LLPS-defective mutations or allosteric inhibitors suppressed complex I and III hyperactivation as well as malignant transformation of SHP2E76K MSCs. These findings reveal that complex I and III hyperactivation driven by SHP2 LLPS promotes malignant transformation of SHP2E76K MSCs and suggest that inhibition of SHP2 LLPS could be a potential therapeutic target for the treatment of activated SHP2-associated cancers.

Advanced Progression for the Heterogeneity and Homeostasis of Intestinal Stem Cells.

Current understanding of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in intestinal stem cells (ISCs) is well established, however, the implications of ISC heterogeneity and homeostasis are poorly understood. Prior studies have provided important evidence for the association between heterogeneity of ISC pools with pathogenesis and therapeutic response of malignant disease. Leveraging the advantages of organoids and single cell RNA sequencing (scRNA-seq), glandular development has been simulated and cell heterogeneity has been clarified. Based on this research, several potential ISCs were identified, such as LGR5 + p27 + quiescent ISCs, LGR5 + Mex3a + slowly proliferating stem cells, and CLU + reverse stem cells. We also illustrated major factors responsible for ISC homeostasis including metabolism-related (LKB1, TGR5, HMGCS2), inflammation-related (IFB-b, IFN2, TNF), and Wnt signaling-related (CREPT, Mex3a, MTG16) factors. ISCs play complex roles in intestinal tumorigenesis, chemoresistance and occasional relapse of colon cancer, which bear discussion. In this review, we focus on novel technical challenges in ISCs fate drawing upon recent research with the goals of clarifying our understanding of complex ISCs, elucidating the integrated intestinal crypt niche, and creating new opportunities for therapeutic development.

Loss of the Novel Mitochondrial Membrane Protein FAM210B Is Associated with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive and challenging disease to treat. Due to the lack of effective early diagnosis and therapy for the illness, it is crucial to identify novel biomarkers that can predict tumor behavior in HCC. In such cases, family with sequence similarity 210 member B (FAM210B) is abundant in various human tissues, but its regulatory mechanisms and role in various tissues remain unclear. In this study, we analyzed the expression pattern of FAM210B in HCC using public gene expression databases and clinical tissue samples. Our results confirmed that FAM210B was dysregulated in both HCC cell lines and HCC paraffin section samples. FAM210B depletion significantly increased the capacity of cells to grow, migrate, and invade in vitro, while overexpression of FAM210B suppressed tumor growth in a xenograft tumor model. Furthermore, we identified FAM210B's involvement in MAPK signaling and p-AKT signaling pathways, both of which are known oncogenic signaling pathways. In summary, our study provides a rational basis for the further investigation of FAM210B as a valuable biological marker for diagnosing and predicting the prognosis of HCC patients.

Structural phase transitions and photoluminescence properties of Eu(3+) doped Ca(2-x)BaxLaNbO6 phosphors.

Crystal structures of the series of double perovskites Ca(2-x)BaxLaNbO6:Eu(3+) phosphors have been examined by powder X-ray diffraction and Rietveld refinements. Ca2LaNbO6 has a monoclinic (P21/n) and Ba2LaNbO6 has a monoclinic (C2/m) structure. The structural phases of Ca(2-x)BaxLaNbO6:Eu(3+) samples are divided into three sections depending on different Ca/Ba ratios: (1) monoclinic phase (P21/n) as Ca2LaNbO6 in the range of x = 0-0.1, (2) mixed phases containing Ca2LaNbO6 and Ba2LaNbO6 between 0.15 and 1.2, and (3) monoclinic phase (C2/m) as Ba2LaNbO6 for x = 1.4-2. Eu(3+) ions act as the structural probes to study the structural phase transitions, and the evolution of the photoluminescence properties and thermal stability behaviours has been also comparatively investigated depending on different structural symmetries from Ca2LaNbO6 to Ba2LaNbO6 phase. The strong red emission from (5)D0-(7)F2 peaking at 618 nm can be found in Ca2LaNbO6:Eu(3+) phosphors, which is attributed to the low crystal field effect of the activator ions located in the highly distorted [LaO8] polyhedra sites. The composition-optimized phosphors can find applications in white light emitting diodes (LEDs).