Exploring the multifaceted role of RASGRP1 in disease: immune, neural, metabolic, and oncogenic perspectives.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

Targeting Tumor Heterogeneity by Breaking a Stem Cell and Epithelial Niche Interaction Loop.

Tumor heterogeneity, the presence of multiple distinct subpopulations of cancer cells between patients or among the same tumors, poses a major challenge to current targeted therapies. The way these different subpopulations interact among themselves and the stromal niche environment, and how such interactions affect cancer stem cell behavior has remained largely unknown. Here, it is shown that an FGF-BMP7-INHBA signaling positive feedback loop integrates interactions among different cell populations, including mammary gland stem cells, luminal epithelial and stromal fibroblast niche components not only in organ regeneration but also, with certain modifications, in cancer progression. The reciprocal dependence of basal stem cells and luminal epithelium is based on basal-derived BMP7 and luminal-derived INHBA, which promote their respective expansion, and is regulated by stromal-epithelial FGF signaling. Targeting this interaction loop, for example, by reducing the function of one or more of its components, inhibits organ regeneration and breast cancer progression. The results have profound implications for overcoming drug resistance because of tumor heterogeneity in future targeted therapies.

Sprouty genes regulate activated fibroblasts in mammary epithelial development and breast cancer.

Stromal fibroblasts are a major stem cell niche component essential for organ formation and cancer development. Fibroblast heterogeneity, as revealed by recent advances in single-cell techniques, has raised important questions about the origin, differentiation, and function of fibroblast subtypes. In this study, we show in mammary stromal fibroblasts that loss of the receptor tyrosine kinase (RTK) negative feedback regulators encoded by Spry1, Spry2, and Spry4 causes upregulation of signaling in multiple RTK pathways and increased extracellular matrix remodeling, resulting in accelerated epithelial branching. Single-cell transcriptomic analysis demonstrated that increased production of FGF10 due to Sprouty (Spry) loss results from expansion of a functionally distinct subgroup of fibroblasts with the most potent branching-promoting ability. Compared to their three independent lineage precursors, fibroblasts in this subgroup are "activated," as they are located immediately adjacent to the epithelium that is actively undergoing branching and invasion. Spry genes are downregulated, and activated fibroblasts are expanded, in all three of the major human breast cancer subtypes. Together, our data highlight the regulation of a functional subtype of mammary fibroblasts by Spry genes and their essential role in epithelial morphogenesis and cancer development.

CD25-targeted antibody-drug conjugate camidanlumab tesirine for relapsed or refractory classical Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) accounts for more than 90% of HL in developed countries. Although the current combined modality therapy make it have a high cure rate, the prognosis for heavily pretreated patients with relapsed or refractory (R/R) cHL remains poor. A novel antibody-drug conjugate (ADC), named camidanlumab tesirine (ADCT-301, Cami), is currently being evaluated for its efficacy and safety in R/R cHL. The primary objective of this review is to examine the current pharmacological properties of camidanlumab tesirine as well as its clinical antitumor activity and safety. Camidanlumab tesirine comprises a human IgG1 anti-CD25 monoclonal antibody HuMax®-TAC, conjugated to a pyrrolobenzodiazepine dimer toxin. Once it bound to CD25-expressing cells, camidanlumab tesirine is internalized by cells and delivers SG3199, then SG3199 irreversibly binds to DNA and forms DNA interstrand crosslinks, ultimately leading to cell death. In the phase 1 study, patients with R/R cHL who received camidanlumab tesirine had an overall response rate (ORR) of 71% and a complete response rate (CRR) of 42%. Additionally, the recommended doses provided in R/R cHL were determined to be 30 and 45 µg/kg. The pivotal phase 2 trial showed significant antitumor activity of camidanlumab tesirine in heavily pretreated R/R cHL patients who failed brentuximab vedotin and programmed death-1 blockade: ORR was 70.1% and CRR was 33.3%, and the median duration of response was 13.7 months. Adverse events such as fatigue, maculopapular rash, and anemia were frequently observed following administration of camidanlumab tesirine. Moreover, camidanlumab tesirine may cause Guillain-Barré syndrome or polyradiculopathy.

Double Signal Amplification Strategy for Dual-Analyte Fluorescent Aptasensors for Visualizing Cancer Biomarker Proteins.

The simultaneous analysis of diversified biomarkers with high sensitivity and in a point-of-care (POC) manner is of great significance for facile and early cancer diagnosis. Herein, we develop a target amplification-assisted ratiometric fluorescence assay (TARFA) platform integrating the dual-amplification strategy and colorimetric readout technology for sensitive and specific detection of two malignancy-associated biomarkers. Meanwhile, the NIR-excited alkaline-earth sulfide nanodots (ASNDs) with an ultrasmall (<10 nm) diameter and tunable emission wavelength are employed to replace commonly UV/visible light-excited fluorescent labels to minimize background interference from the sample matrix. Unique advantages of the ASNDs, together with superiority of consecutive signal amplification of enzymatic target recycling (ETR) and hybridization chain reaction (HCR), realize the pg/mL-range detection limit in specifically recognizing the vascular endothelial growth factor (VEGF) and soluble interleukin-6 receptors (sIL-6R). The combination detection of the dual analyte exhibits an improved sensitivity for cancer diagnosis. The addition of the target biomarkers leads to an increasingly ratiometric RGB signal, and quantification based on the ratio-dependent signal is more reliable rather than measuring the absolute RGB signals. Moreover, perceptible color transformation makes the TARFA platform competent for visual analysis of the target analytes as convenient as reading the pH indicator strip, and hue-based image analysis also improves the method with fine precision by quantitatively identifying the visual color. This work provides a new kind of NIR-excited aptasensing platform with a low detection limit, high throughput, and great portability, which also highlights the potential of the ASNDs in biomolecular fluorescent labeling.

RasGRP1 is a target for VEGF to induce angiogenesis and involved in the endothelial-protective effects of metformin under high glucose in HUVECs.

Impaired angiogenesis in endothelial cells is a hallmark of diabetes vascular complications. Ras guanine-releasing protein 1 (RasGRP1) is a guanine nucleotide exchange factor for Ras, and its role in endothelial angiogenesis has not been investigated. Given the importance of Ras in vascular endothelial growth factor (VEGF)-induced angiogenesis, we hypothesized that RasGRP1 may be a critical pathway downstream of VEGF and involved in endothelial angiogenesis. Furthermore, we investigate whether RasGRP1-dependent VEGF signaling was downregulated under high glucose conditions mimicking diabetes and required for the endothelial protective action of metformin in human umbilical vein endothelial cells (HUVECs). HUVECs were transfected with either RasGRP1 small interfering RNA (siRNA) or pEnter-RasGRP1 plasmid to down- and upregulate RasGRP1 expression before different treatments, such as added VEGF or not, exposed to high glucose (35 mM) or normal glucose (5 mM) in the presence or absence of metformin. Expression of VEGF, RasGRP1, and their signaling targets were analyzed by Western blot; migration and tube formation were detected by transwell chamber assay and Matrigel angiogenesis assay, respectively. Knockdown of RasGRP1 significantly attenuated VEGF-induced migration and tube formation activities of HUVECs and activation of AKT pathway. The expression of VEGF, RasGRP1, and AKT phosphorylation was downregulated in HUVECs exposed to high glucose compared with normal glucose, whereas metformin upregulated the RasGRP1-dependent VEGF signaling and ameliorates the impaired angiogenesis caused by high glucose. RasGRP1 is involved in the VEGF-induced angiogenesis and the pro-angiogenesis effects of metformin under hyperglycemia. © 2019 IUBMB Life, 71(9):1391-1400, 2019.