Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis.

Metastasis is the primary cause of cancer-related mortality. Tumor cell interactions with cells of the vessel wall are decisive and potentially rate-limiting for metastasis. The molecular nature of this cross-talk is, beyond candidate gene approaches, hitherto poorly understood.

Alternatively Spliced Form of Angiopoietin-2 as a New Vascular Rheostat.

Angiopoietin (ANPGT)-TIE signaling serves as a critical regulator of vessel maturation controlling vascular quiescence, maintenance, and homeostasis (primarily through ANGPT1-TIE2 signaling), as well as enabling vascular plasticity and responsiveness to exogenous cytokines (primarily through antagonistically acting ANGPT2). An alternatively spliced form of ANGPT2 (ANGPT2) was first reported 20 years ago. Yet, little is known to this day about its biological functions.

Preclinical validation of a novel metastasis-inhibiting Tie1 function-blocking antibody.

The angiopoietin (Ang)-Tie pathway has been intensely pursued as candidate second-generation anti-angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2-targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelial-specific genetic deletion has previously been shown to result in a strong reduction in metastatic growth.

[Functional Analysis of Apoptosis Signal-regulating Kinase Family in a Murine Model of Tumor Metastasis].

Stress-responsive signaling pathways convert cellular stresses into various physiological responses, such as cell proliferation, apoptosis, and inflammation. Signal pathway dysfunction thus induces abnormal cellular behaviors that may lead to tumorigenesis and tumor progression, including metastasis. Tumor metastasis is the spread of tumor cells from primary lesions to other distant tissues/organs.

ASK1 facilitates tumor metastasis through phosphorylation of an ADP receptor P2Y in platelets.

Tumor metastasis is the major cause of deaths in cancer patients and is modulated by intertwined stress-responsive signaling cascades. Here we demonstrate that deletion of stress-responsive apoptosis signal-regulating kinase 1 (Ask1) in platelets results in unstable hemostasis and drastic attenuation of tumor lung metastasis, both of which are attributable to platelet dysfunction. Platelet-specific deletion of Ask1 in mice leads to defects in ADP-dependent platelet aggregation, unstable hemostasis and subsequent attenuation of tumor metastasis.

ASK family and cancer.

Cancer is a major problem in public health and is one of the leading causes of mortality worldwide. Many types of cancer cells exhibit aberrant cellular signal transduction in response to stress, which often leads to oncogenesis. Mitogen-activated protein kinase (MAPK) signal cascades are one of the important intracellular stress signaling pathways closely related to cancer.

In vivo gene manipulation reveals the impact of stress-responsive MAPK pathways on tumor progression.

It has been widely accepted that tumor cells and normal stromal cells in the host environment coordinately modulate tumor progression. Mitogen-activated protein kinase pathways are the representative stress-responsive cascades that exert proper cellular responses to divergent environmental stimuli. Genetically engineered mouse models and chemically induced tumorigenesis models have revealed that components of the MAPK pathway not only regulate the behavior of tumor cells themselves but also that of surrounding normal stromal cells in the host environment during cancer pathogenesis.

Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5.

Regulated intramembrane proteolysis is a widely conserved mechanism for controlling diverse biological processes. Considering that proteolysis is irreversible, it must be precisely regulated in a context-dependent manner. Here, we show that phosphoglycerate mutase 5 (PGAM5), a mitochondrial Ser/Thr protein phosphatase, is cleaved in its N-terminal transmembrane domain in response to mitochondrial membrane potential (ΔΨ(m)) loss.