PI3K-dependent PI3P production recruits trafficking regulators Rab5a and GPA5 to dense vesicles and ensures efficient post-Golgi transport of glutelins in

PubMed link

Why some tumors respond to immunotherapy (“hot” tumors) while others remain resistant (“cold” tumors) is a central challenge in oncology. Elevated RAB5A-dependent endocytosis drives tissue fluidization during the transition to invasive breast carcinoma, but its immunological consequences are unclear. Here we show that RAB5A-driven fluidization induces a mechano-metabolic stress response that disrupts the AMPK–AKAP1–DRP1 mitochondrial fission pathway, causing mitochondrial elongation. RAB5A vesicles interact with hyperfused mitochondria and promote BAX/BAK-dependent pore formation, leading to limited mitochondrial outer membrane permeabilization. This sub-lethal event is amplified by palmitoylated GASDERMIN A oligomerization on mitochondria, establishing a positive feedback loop. The resulting release of mitochondrial DNA activates the cGAS–STING innate immune pathway and drives a hyperinflammatory state. Consequently, RAB5A-expressing tumors in immunocompetent mice grow more slowly, sh

Read the full paper: RAB5A regulates cell proliferation and lipid metabolism by modulating mitochondrial ROS via AMPK signaling pathway in ovarian granulosa cells

RAB5A-mediated unjamming enhances active wetting through distinct biomechanical processes: a) upregulation of specific integrin subunits, enhanced focal adhesions kinetics and activity; b) supracellu...

RAB5A-mediated unjamming enhances active wetting through distinct biomechanical processes: a) upregulation of specific integrin subunits, enhanced focal adhesions kinetics and activity; b) supracellular organization relying on nanoscale integrin clustering, and the formation of a stiff and collective actin cable; and c) softening of the spheroid core driving the escape from a jammed state, and decreased compressive stress exerted on the substrate. Abstract Unjamming transitions from a solid-like to a fluid-like state are a gateway to breast epithelial cancer invasion. However, the mechanical interplay between phase transitions and dimension transitions, in particular wetting, remains elusive, despite being critical for understanding the onset of metastatic dissemination. This study shows that unjamming, mediated by the RAB5A GTPase, alters carcinoma spheroid fluidity, rigidity, and rewires adhesion mechanics to drive supracellular active wetting as a new mode of tumor expansion. Spheroid fluidification enhances the selective expression of integrin subunits and increases focal adhesion dynamics, inducing a fluid-like spreading behavior on specific matrix ligands. Notably, nanoscale regulation of integrin clustering can select for distinct phase transitions at the collective scale upon wetting. In this framework, fluidized spheroids polarize into cohesive “supracells”, and maintain a stiff peripheral actin bundle as measured by nanomechanical mapping. Furthermore, a combination of Brillouin microscopy and 2.5D traction force analysis reveals a mechanical switch within the spheroid core, characterized by significant cell softening and a reduction in compressive forces exerted on the substrate, thereby mimicking the wetting of a liquid droplet. These findings establish unjamming-driven active wetting as a key mechanism to comprehend the molecular and biophysical underpinnings of solid tumor invasion.

Background Few researches have investigated the molecular mechanism responsible for the age-related loss of the pelvic floor muscle (PFM) mass and functionality—a pivotal contributor to pelvic organ...