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Li, C.-W.

Publications and source records attributed to Li, C.-W..

2 recordsLinked to original sources
bioRxiv2024

Pexidartinib plus FLT3-directed CAR-Macrophage for the treatment of FLT3-ITD-mutated acute myeloid leukemia in preclinical model

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations occur in about 25%-30% of AML cases and are associated with adverse prognosis. Recent advances indicate that M2-like leukemia-associated macrophages (M2-LAM) are highly infiltrated in the bone marrow of FLT3-ITD+ AML patients; however, the underlying mechanisms and therapeutic implications are still elusive. Herein, we reveal that conditioned medium from FLT3-ITD+ MOLM-13 AML cells polarized M2-LAM and impaired their phagocytic activities. Unexpectedly, co-culture of M2-LAM protected MOLM-13 cells from the treatment of FLT3 inhibitor quizartinib by activating their FLT3 signaling pathway. Pharmaceutically, FLT3/CSF1R dual inhibitor pexidartinb effectively suppressed M2-LAM, reduced leukemic burden, and prolonged the survival of MOLM-13-xenografted mice. To enhance the phagocytic activities of macrophages, FLT3-directed chimeric antigen receptor-engineered macrophages (FLT3L-CAR-Macrophage) were generated using FLT3 ligand (FLT3L) as the recognizing domain of CAR. Transfection of THP-1 monocytic cells-or umbilical cord blood mononuclear cells-derived macrophages with FLT3L-CAR-encoding mRNA enhanced their phagocytic activities to MOLM-13 cells in vitro. Consistently, FLT3L-CAR-Macrophage differentiated from FLT3L-CAR-expressing THP-1 cells effectively phagocytosed MOLM-13 cells in vitro, reduced leukemic burden and prolonged the survival of MOLM-13-xenografted mice. Importantly, treatment of pexidartinib resulted in upregulation and surface localization of FLT3-ITD protein in MOLM-13 cells, sensitized MOLM-13 cells to the treatment of FLT3L-CAR-Macrophage in vitro, and synergized with FLT3L-CAR-Macrophage to further reduce leukemic burden in MOLM-13-xenografted mice. Together, our data indicate that pexidartinib plus FLT3L-CAR-Macrophage could be a promising therapeutic strategy for the treatment of FLT3-ITD+ AML in preclinical model which warrants further investigation. Graphical AbstractPexidartinib plus FLT3L-CAR-M{varphi} for the treatment of FLT3-ITD+ AML in preclinical model. Pexidartinib suppressed AML growth, reduced M2-LAM, increased FLT3 surface expression and synergized with FLT3L-CAR-M{varphi} to target FLT3-ITD+ AML in vitro and in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/615313v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1e7c0f4org.highwire.dtl.DTLVardef@2cdf6eorg.highwire.dtl.DTLVardef@e84borg.highwire.dtl.DTLVardef@1929d28_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2022

Circulating androgen regulation by androgen-catabolizing gut bacteria in male mouse gut

Abnormally high circulating androgen levels have been considered a causative factor for benign prostatic hypertrophy and prostate cancer. Recent studies suggested that gut bacteria can alter sex steroid profile of host; however, the underlying mechanisms and bacterial taxa remain elusive. Thauera sp. strain GDN1 is an unusual betaproteobacterium capable of aerobic and anaerobic androgen catabolism in environmental conditions (37{degrees}C) resembling the mammalian gut. The strain GDN1 administration to C57BL/6J mice through oral gavage profoundly affected gut bacterial community, along with an approximately 50% reduction in serum androgen level in male mice. Our RT-qPCR results revealed the differential expression of aerobic and anaerobic androgen catabolic genes in the mouse ileum (microaerobic) and caecum (anaerobic), respectively. Furthermore, androgenic ring-cleaved metabolites were detected in the mouse fecal extract. This study discovered that androgen serves as a carbon source of gut microbes and that androgen-catabolizing gut bacteria can modulate host circulating androgen levels. HighlightsO_LIThauera sp. strain GDN1 administration through oral gavage regulated mouse serum androgen levels. C_LIO_LIThe biochemical, genetic, and metabolite profile analyses revealed the occurrence of bacterial androgen catabolism in the mouse gut. C_LIO_LIAndrogen catabolism proceeds through the O2-dependent and O2-independent catabolic pathways in mouse ileum and caecum, respectively. C_LIO_LIA possibility to harness Thauera sp. strain GDN1 as a functional probiotic to treat hyperandrogenism. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/500890v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@515126org.highwire.dtl.DTLVardef@a696faorg.highwire.dtl.DTLVardef@1020beforg.highwire.dtl.DTLVardef@15da175_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefHsiao et al. found that oral administration of androgen-catabolizing Thauera species regulated mouse serum androgen level. They characterized the gut microbe-mediated androgen catabolism through genetic and biochemical analyses. Their discovery portends a possibility of harnessing androgen-catabolic gut bacteria as functional probiotics to treat hyperandrogenism.

microbiology↗