Biology subjects

Huo, Y.-M.

Publications and source records attributed to Huo, Y.-M..

3 recordsLinked to original sources

bioRxiv2026

L-Lactate reprograms tumor-associated macrophages to drive pancreatic cancer progression via BCL3 lactylation

Metabolic reprogramming fuels pancreatic ductal adenocarcinoma (PDAC) malignancy, creating a nutrient-deprived and waste-rich microenvironment. How this extreme metabolic pressure dictates the phenotypic remodeling of infiltrating immune cells remains largely unclear. Metabolomic profiling of PDAC reveals that robust tumor glycolysis proceeds without a commensurate accumulation of extracellular lactate. Integrated single-cell profiling and tissue multiplex immunofluorescence demonstrate that tumor-associated macrophages (TAMs) act as the primary consumers of tumor-secreted lactate. The uptake of L-lactate directs macrophages toward a pro-tumorigenic state through site-specific L-lactylation of the transcriptional co-regulator BCL3 at lysine 21 (K21). Functioning as a molecular switch, K21 lactylation triggers BCL3 nuclear translocation and enhances its interaction with the NF-{kappa}B p50 subunit. The ensuing BCL3-p50 complex competitively displaces the pro-inflammatory p65 subunit, rewiring the transcriptional output to suppress inflammation and enforce tumor-supporting networks. In vivo, macrophage-specific expression of a lactylation-deficient BCL3 mutant (K21R) abolishes lactate-driven phenotypic shifts and restricts tumor growth. Clinically, a BCL3-lactylated macrophage signature spatially correlates with CD8+ T cell exclusion and predicts poor patient survival, providing a strong rationale for targeting the BCL3-lactylation axis to reverse TAM-driven PDAC progression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/710237v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@173159eorg.highwire.dtl.DTLVardef@9065f3org.highwire.dtl.DTLVardef@153e0aorg.highwire.dtl.DTLVardef@9c2678_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Mechanical cues of extracellular matrix determines tumor innervation

Peripheral tumors can establish local autonomic and sensory nerve networks, termed as tumor innervation (TIN), to support tumorigenesis and metastasis. While nerve dependence in cancers is well-established, the mechanisms governing TIN remain unclear. Here, we report that extracellular matrix (ECM) stiffness, a major mechanical abnormality in the tumor microenvironment (TME), is an essential contributor of TIN. In preclinical models, reducing lysyl oxidase-mediated ECM crosslinking lowers tissue stiffness and TIN in pancreatic cancer, while inflammation-induced matrix stiffening boosts the hyperinnervation of the pancreatic precursor lesions. Mechanistically, {beta}1-containing integrins sense the mechanical cues exerted by ECM stiffness, and the translational co-activator YAP1 acts as an essential nuclear relay to induce the expression of neurotropic genes, particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). 3D imaging of the whole cleared pancreas reveals that blockade of mechanosensor integrin {beta}1 or pharmacological inhibition of the mechanotransducer YAP1 effectively reduces TIN. In clinical settings, tumor samples with a dense, crosslinked, and stiffened ECM exhibit significant TIN. In summary, these findings identify ECM stiffness as an important driver of TIN and suggest that targeting integrin {beta}1/YAP1-dependent mechanotransduction may counteract TIN.

neuroscience↗

bioRxiv2023

A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer

BACKGROUND & AIMSPDAC is characterized by significant matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, it is not clear the connection between matrix stiffness and the Warburg effect and the mechanisms of action in tumor progression. METHODSThe relationship between matrix stiffness and the Warburg effect was investigated from clinical, cellular, and bioinformatical perspectives. The ChIP and luciferase reporter gene assays were used to clarify the regulation mechanism of matrix stiffness on the expression of CLIC1. The expression profile and clinical significance of CLIC1 were determined in GEO datasets and a TMA. Loss-of-function and gain-of-function technics were used to determine the in vitro and in vivo functions of CLIC1. GSEA and western blotting revealed the underlying molecular mechanisms. RESULTSPDAC matrix stiffness is closely associated with the Warburg effect, and CLIC1 is a key molecule connecting tumor matrix stiffness and the Warburg effect. Increased CLIC1 expression induced by matrix stiffness correlates with poor prognosis in PDAC. CLIC1 acts as a promoter of glycolytic metabolism and facilitates tumor growth in a glycolysis-dependent manner. Mechanistically, CLIC1 inhibits the hydroxylation of HIF1 via ROS, which then increases the stability of HIF1. Collectively, PDAC cells can sense extracellular matrix stiffness and upregulate the expression of CLIC1, which facilitates the Warburg effect through ROS/HIF1 signaling, thereby supporting tumor growth. CONCLUSIONSIn the context of tumor therapy, targeted approaches can be considered from the perspectives of both extracellular matrix stiffness and tumor metabolism, of which CLIC1 is one of the targets.

cancer biology↗