Biology subjects

Fei, F.

Publications and source records attributed to Fei, F..

3 recordsLinked to original sources

bioRxiv2026

Cholesterol constrains pore formation by mammalian gasdermins

Pyroptosis is a lytic form of cell death executed by gasdermin pores. Through a CRISPR screen to uncover macrophage genes required for gasdermin D (GSDMD) pore activity, we identify the endosome adaptor Rabgef1 as a positive regulator of pore formation. Rabgef1 deficiency preserves NT-GSDMD membrane binding but prevents NT-GSDMD oligomerization and lytic death. Mechanistic analyses revealed that Rabgef1 deficiency is associated with an overabundance of cholesterol in the plasma membrane. Cholesterol depletion or redistribution through multiple approaches restores GSDMD oligomerization and pyroptosis. The Rabgef1-mediated control of membrane cholesterol and pore formation was found to be a general regulator of the gasdermin family. In cancer cells, organoids, and tumors, cholesterol reduction sensitizes resistant cells to GSDME pyroptosis driven by synthetic mRNAs, chemogenetic induction, and chemotherapy treatment. These results establish membrane cholesterol content as an endogenous checkpoint for gasdermin-mediated pyroptotic cell death during the execution phase, with implications for metabolic disease and cancer immunotherapy.

immunology↗

bioRxiv2021

Overcoming microenvironment-mediated chemoprotection through stromal Galectin-3 inhibition in acute lymphoblastic leukemia

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells including a dose-dependent reduction of viability and proliferation, induction of apoptosis and, importantly, inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

cancer biology↗

bioRxiv2021

Cell-Intrinsic and Extrinsic Effects of Galectin-1 and Galectin-3 in B-Cell Precursor Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemias arising from the malignant transformation of B-cell precursors (BCP-ALLs) are protected against chemotherapy by both intrinsic factors as well as by interactions with bone marrow stromal cells. Galectin-1 and Galectin-3 have overlapping expression patterns and potentially common functions in these cells. We used Galectin-1 and Galectin-3 double null mutant murine BCP-ALL cells to examine the effect of loss endogenous Galectins. We also tested the effect of dual Galectin inhibition by use of plant-derived natural compounds GM-CT-01 and GR-MD-02 in human BCP-ALL cells in co-culture with stroma. Transformed wild type and Galectin-1 x Galectin-3 double knockout BCP-ALL cells were similar in immunophenotype and active intracellular signaling. However, compared to wild type cells, they showed impaired migration, significantly reduced proliferation and increased sensitivity to drug treatment. GM-CT-01 and GR-MD-02 attenuated intracellular signal transduction and sensitized human BCP-ALL cells to chemotherapy including vincristine and the targeted tyrosine kinase inhibitor nilotinib. Our data show endogenous and extracellular Galectins contribute positively to the growth and survival of BCP-ALL cells. Strategies that would efficiently ablate these two Galectins at both locations would decrease microenvironmental protection and reduce BCP-ALL persistence in the protective bone marrow niche after chemotherapy.

cancer biology↗