Biology subjects

Li, M. X.

Publications and source records attributed to Li, M. X..

3 recordsLinked to original sources

bioRxiv2024

Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity

Glioblastoma (GBM) exhibits developmental programs and marked cellular heterogeneity, yet how these features are organized into connected lineage hierarchies remains unclear. Here we identify a rare tumor-intrinsic population, termed the neurovascular progenitor (NVP), that occupies an intermediate position between the major GBM organizational axes. NVP cells co-express neural progenitor and perivascular transcriptional features, are consistently detected across independent patient cohorts, retain canonical GBM copy-number alterations, and localize in situ in both vessel-associated and parenchymal niches. Using direct-from-patient lineage tracing in a human organoid tumor transplantation system, we show that individual NVP cells clonally generate both neural-like and mesenchymal/vascular-like malignant progeny, providing a concrete lineage link between states that are commonly considered mutually exclusive. Despite comprising [~]1% of tumor cells, NVP-derived lineages account for a majority of observed tumor cell types and disproportionately contribute to cycling compartments. Orthogonally, ablation of NVP-associated programs in an in vivo GBM model remodels tumor composition, elicits compensatory progenitor states, and significantly prolongs survival. Together, these findings position NVP as a fate-restricted yet highly influential lineage intermediate that serves as a functional bridge and organizational nexus within GBM hierarchies, linking population-level lineage architecture to the behavior of a specific progenitor cell type.

cancer biology↗

bioRxiv2023

Molecular definition of the BAK:VDAC2 interaction as a target to manipulate apoptosis

BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial porin VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, whilst interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK, and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease, or to promote BAK-mediated apoptosis for cancer therapy.

cell biology↗

bioRxiv2023

Immuno-Engineered Mitochondria for Efficient Therapy of Acute Organ Injuries via Modulation of Inflammation and Cell Repair

Acute organ injuries represent a major public health concern, and despite recent advances in organ support therapy, managing patients with organ failure stemming from such injuries remains a formidable challenge. The pathogenesis of acute organ injuries is driven by a cascade of inflammatory reactions and mitochondrial dysfunction-mediated cell damage, two interrelated events that fuel a vicious cycle of disease progression. In this study, we engineered neutrophil membrane-fused mitochondria (nMITO) that inherit the injury-targeting and broad-spectrum anti-inflammatory activities from neutrophil membrane proteins while retaining the cell-repairing activity of mitochondria. We demonstrated that nMITO can effectively block the inflammatory cascade and replenish mitochondrial function to simultaneously modulate these two key mechanisms in diverse acute organ injuries. Furthermore, by virtue of the {beta}-integrin inherited from neutrophils, nMITO exhibit selective homing to injured endothelial cells and can be efficiently delivered to damaged tissue cells via tunneling nanotubes, amplifying their regulatory effects on local inflammation and cell injury. In mouse models of acute myocardial injury, acute liver injury, and acute pancreatitis, nMITO effectively ameliorated immune dysfunction and repaired damaged tissues. Our findings suggest that nMITO represents a promising therapeutic strategy for managing acute organ injuries.

bioengineering↗