“P2RY8-son” break of tolerance promotes SLE

In this issue of JEM, He et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211004) associate novel P2RY8 genetic variants to lupus, expanding the field of monogenic autoimmunity. The authors demonstrate that P2RY8 prevents the expansion of DNA-reactive B cells by restraining B cell mobility and activation within the germinal center.

Type V collagen alpha 1 chain promotes the malignancy of glioblastoma through PPRC1-ESM1 axis activation and extracellular matrix remodeling

Glioblastoma (GBM) is a fatal cancer. Existing therapies do not have significant efficacy for GBM patients. Previous studies have shown that the collagen family is involved in the regulation of the extracellular environment of cancer cells, and these conditions could become an important factor for effective treatment. Therefore, we screened various collagen types and observed that the type V collagen α1 chain (COL5A1) gene plays a pivotal role in GBM. We further examined whether the overexpression of COL5A1 is common in mesenchymal subtypes and is related to the survival rate of GBM patients through several in silico cohorts. In addition, our cohort also showed a consistent trend in COL5A1 protein levels. Most importantly, we validated the cell mobility, metastatic ability and actin polymerization status caused by COL5A1 with two-way models. Based on these results, we established a transcriptomics dataset based on COL5A1. Moreover, PPRC1, GK and ESM1 were predicted by ingenuity pathway analysis (IPA) to be transcription factors or to participate downstream. We investigated the involvement of COL5A1 in extracellular remodeling and the regulation of actin filaments in the metastasis of GBM. Our results indicate that the COL5A1−PPRC1−ESM1 axis may represent a novel therapeutic target in GBM.

Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

Iodide uptake and the metabolism of thyroid cells are regulated by thyrotropin (TSH)-TSH receptor (TSHR) signaling. Thus, it is necessary to elevate serum TSH levels by T4 withdraw or rTSH administration to facilitate radioiodide (131I) therapy for differentiated thyroid cancer (DTC). However, non-iodide-avid metastases of DTC which is dedifferentiated do not respond to stimulation by high levels of TSH, suggesting abnormal TSH-TSHR signal transduction in cancer cells. In addition, PI3K/AKT/mTOR signaling activation has been shown to be associated with the dedifferentiated phenotype of thyroid cancer, but the mechanism remains elusive. Therefore, in this study, we aimed to explore the role of abnormal TSH-TSHR signaling activation in regulating iodide uptake and cell mobility in thyroid cancer and its relationship with PI3K/AKT/mTOR signaling. We found that in thyroid cancer cells, TSH binds TSHR coupled to the Gα12/13 protein and then activates RhoA through interacting with leukemia associated RhoA guanine exchange factor (LARG). This results in a promigration tumorigenic phenotype independent of canonical TSHR-GαS signaling that regulates the expression of molecules involved in iodine uptake and metabolism. We observed that signaling pathways downstream of Gα12/13 signaling were increased, while that of Gαs signaling was decreased in thyroid cancer cells undergoing dedifferentiation compared to control cells following stimulation with different levels of TSH. PI3K/AKT/mTOR signaling activation enhanced Gα12/13 signaling through increasing LARG levels but also inhibited the expression of molecules downstream of Gαs signaling, including thyroid-specific molecules, and iodide uptake. In summary, our results demonstrate the noncanonical activation of TSH-TSHR signaling and its role in increasing the cell mobility and dedifferentiation of thyroid cancer through crosstalk with PI3K/AKT/mTOR signaling.

B7-H4 Expression is Upregulated by PKCδ Activation and Contributes to PKCδ-Induced Cell Mobility in Colorectal Cancer

Background B7-H4 is overexpressed in colorectal cancer (CRC) and plays important roles in tumour growth and immunosuppression. However, the exact mechanism that regulates B7-H4 expression remains largely unknown. Protein kinase δ (PKCδ) plays a significant role in a range of cancers, including CRC. Here, we investigated whether PKCδ regulates the expression of B7-H4 in CRC.Methods By using immunohistochemical and immunofluorescence (IF) staining, we analysed the expression of B7-H4 and phospho-PKCδ (p-PKCδ) in 225 colorectal tumour samples, and the clinical significance of these expression patterns was determined. In vitro experiments were performed with the CRC cell lines HCT116 and SW620 to detect the effect of PKCδ activation on B7-H4 expression.Results B7-H4 expression was significantly correlated with p-PKCδ expression (r=0.378, P<0.001) in tumour tissues. The co-expression of p-PKCδ and B7-H4 was significantly associ­ated with moderate/poor differentiation (P=0.024), lymph node metastasis (P=0.001) and an advanced Dukes’ stage (P=0.002). Western blot analysis showed that TPA increased B7-H4 levels in a concentration-dependent manner and rottlerin also abrogated TPA-induced B7-H4 enhancement. The expression of B7-H4 and p-STAT3 were significantly reduced by PKCδ-specific siRNA. Moreover, STAT3 inhibitor cryptotanshinone significantly decreased B7-H4 protein levels in HCT116 cells. Knockdown of B7-H4 or PKCδ expression suppressed cell migration and mobility.Conclusion B7-H4 expression was significantly correlated with p-PKCδ expression in CRC samples. B7-H4 expression was upregulated by STAT3 activation via PKCδ and played roles in PKCδ-induced cancer cell mobility and metastasis.

Invasion fronts and adaptive dynamics in a model for the growth of cell populations with heterogeneous mobility

We consider a model for the dynamics of growing cell populations with heterogeneous mobility and proliferation rate. The cell phenotypic state is described by a continuous structuring variable and the evolution of the local cell population density function (i.e. the cell phenotypic distribution at each spatial position) is governed by a non-local advection–reaction–diffusion equation. We report on the results of numerical simulations showing that, in the case where the cell mobility is bounded, compactly supported travelling fronts emerge. More mobile phenotypic variants occupy the front edge, whereas more proliferative phenotypic variants are selected at the back of the front. In order to explain such numerical results, we carry out formal asymptotic analysis of the model equation using a Hamilton–Jacobi approach. In summary, we show that the locally dominant phenotypic trait (i.e. the maximum point of the local cell population density function along the phenotypic dimension) satisfies a generalised Burgers’ equation with source term, we construct travelling-front solutions of such transport equation and characterise the corresponding minimal speed. Moreover, we show that, when the cell mobility is unbounded, front edge acceleration and formation of stretching fronts may occur. We briefly discuss the implications of our results in the context of glioma growth.

Fabrication of smart titanium implants by femtosecond laser synthesis.

A 3-D nanostructure particle network of TiO2, TiO, Ti3O oxide nanoparticles is synthesized by ultra-short pulsed femtosecond laser irradiation from a Grade 2 pure titanium substrate. This study investigated the properties of the resulting nanostructure and underneath phase transformed surface for biomaterial applications. Controlled tuning of surface chemistry and phases of the 3-D network were found to directly influence the cell mobility. The presented findings support a previously unrealized capacity by nano-core shell like particles and its phases for reducing cell proliferation on a biomaterial. Both osteoblast and fibroblast cells improved controllability and anisotropic migration with the developed nanostructure. The corresponding oxide phases which influenced this controllability was analysed in detail with possible potential in health care industry. The results suggest an effective means to improve biomaterial life thereby increasing implant life.