bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.12.12.628238

Galectin-1 Modulates Hepatocellular Carcinoma Response to Thermal Ablation Through Regulating Glycolysis

Nguyen, T.·Shin, Y.·Pham, J.·Ruppa, A.·Chen, P.-c.·Mirmohammadi, H.·Lu, D. S. K.·Raman, S. S.·Chiang, J.
View original source ↗Export metadata ↓

Abstract

I.Background & AimsThermal ablation is the standard of care treatment modality with curative intent for early-stage hepatocellular carcinoma (HCC), but its efficacy remains moderately limited-- with up to 40% of HCC patients experiencing local recurrence post-treatment. This study aimed to evaluate the prognostic value of galectin-1 (Gal-1) in predicting thermal-ablation responsiveness. We then evaluated the therapeutic potential of targeting Gal-1 in inhibition of glycolysis and subsequently enhancing thermal-ablation efficacy. MethodsLiquid-Chromatography Mass-Spectrometry (LC-MS) was employed to analyze proteomic profiles of retrospectively collected pre-ablation FFPE samples of known thermal-ablation responders and nonresponders. An in-vitro thermal peri-ablation model was established using a heated water bath. Gal-1 inhibition via OTX008 or knockdown was utilized to investigate hyperthermic sensitivity. Hyperthermia-resistant SNU449 cells were used to establish an orthotopic murine model to evaluate the combination therapy of OTX008 and thermal ablation. Harvested tumors were analyzed by LC-MS to determine their metabolic profiles. ResultsThis study revealed that responders had significantly longer tumor progression-free survival compared to nonresponders (57.0{+/-}1.6 (median not reached) versus 8.3{+/-}0.5 months (median: 13.6 months), p<0.001). Moreover, responders were found to have significant downregulation of Gal-1 expression compared to that of nonresponders. Gal-1 inhibition or knockdown markedly increased hyperthermic sensitivity in hyperthermia-resistant HCC SNU449 cells. Targeting Gal-1 by OTX008 in combination with thermal ablation significantly reduced SNU449-derived tumor growth compared to the thermal-ablation alone group in vivo. Metabolomic analysis revealed decreased glycolytic metabolites, fructose 1,6-bisphosphate, 3-phosphoglycerate and phosphoenolpyruvate, while western blot analysis showed decreased Gal-1 expression in the combined treatment group compared to monotherapy thermal ablation or OTX008 treatment. ConclusionsGal-1 overexpression correlates with thermal-ablation nonresponsiveness, and targeting Gal-1 enhances thermal-ablation efficacy by inhibiting glycolysis. Impact and ImplicationsDespite being a standard-of-care treatment for early-stage HCC, thermal ablation has a high local recurrence rate of approximately 40%. While thermal ablation can lead to cellular death in the central-treatment zone, its metabolic impact on cells in the peri-ablational region remains unclear. This study shows the direct association between Gal-1 overexpression and thermal-ablation nonresponsiveness. Moreover, it found that Gal-1 inhibition or knockdown increased hyperthermia sensitivity in vitro. Targeting Gal-1 in combination with thermal-ablation significantly reduced hyperthermia-resistant SNU449 tumor growth by inhibiting glycolysis in vivo. These findings suggest that the efficacy of thermal ablation in HCC can be enhanced by pharmacologically inhibiting Gal-1. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/628238v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@18788ccorg.highwire.dtl.DTLVardef@1261839org.highwire.dtl.DTLVardef@5d57org.highwire.dtl.DTLVardef@1f00b2a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIProfiling pre-ablation HCC biopsies reveals Galectin-1 as a key prognostic biomarker for response prediction in thermal ablation C_LIO_LITargeting Galectin-1 with a selective inhibitor (OTX008) enhances the efficacy of thermal ablation in HCC C_LIO_LIGalectin-1 modulates thermal-ablation response via regulating glycolysis in HCC C_LI

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Nguyen, T., Shin, Y., Pham, J., Ruppa, A., Chen, P.-c., Mirmohammadi, H., Lu, D. S. K., Raman, S. S., Chiang, J.. 2024-12-13. Galectin-1 Modulates Hepatocellular Carcinoma Response to Thermal Ablation Through Regulating Glycolysis. https://doi.org/10.1101/2024.12.12.628238

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Ex vivo human tumor slices more accurately predict patient responses to an oncolytic virus than in vivo mouse models

Immunotherapies, including oncolytic viruses (OV), are promising therapies that can enhance anti-tumor immune responses. However, preclinical success of immunotherapies in mouse models has not always translated to clinical benefit in cancer patients. This study compared preclinical efficacy and mechanism of action for ASP9801, a vaccinia virus expressing IL-7 and IL-12, using mouse models of colorectal cancer (CRC) in vivo and in human organotypic tumor slice models ex vivo. The murine surrogate for ASP9801 significantly reduced tumor volumes in treated and abscopal tumors in two different CRC models in vivo (MC38 and RO100). Treatment efficacy was accentuated when combined with anti-PD1 treatment, and single-cell RNA sequencing analysis revealed depletion of tumor cells and increased T cell infiltration and activation in both treated and abscopal tumors. However, human tissue analysis ex vivo (E-slices) using PDX models and patient samples showed that ASP9801 is not effective in CRC, consistent with clinical trial results. On the other hand, ASP9801 was highly effective in GBM, indicating indication-specific efficacy of ASP9801, and how E-slice assays can be used to identify treatment-sensitive indications. This study demonstrates the superiority of E-slices over mouse models for predicting clinical response and its utility in planning clinical trials.

cancer biology↗
bioRxiv2026

Immune-cell depleted diffuse large B-cell lymphomas have reduced expression of MHC class I

Immunotherapy has transformed treatment for many cancers. In the aggressive and genetically heterogeneous diffuse large B-cell lymphoma (DLBCL), CD19 CAR T-cell therapy is highly effective, whereas immune checkpoint blockade has shown limited benefit. Loss of MHC expression is a common mechanism to escape T-cell cytotoxicity, and loss of MHC class I (MHC-I) and II are frequent in DLBCL. We applied imaging mass cytometry to diagnostic biopsies from younger, high-risk DLBCL patients to map the tumor microenvironment (TME) spatial architecture in relation to tumor cell MHC expression, mutational status, transcriptomic and proteomic profiles. Neighborhood analyses identified four TME subtypes: immune-cell depleted and three immune-infiltrated types (mixed, CD4 T cell-rich, CD8 T-cell/macrophage-rich). Depleted cases had shorter overall survival (p = 0.033) and increased expression of proteins involved in DNA replication and proliferation markers compared to infiltrated cases. Tumor cell MHC-I expression was heterogeneous. Cases with low frequency of MHC-I-pos tumor cells were enriched for the depleted TME type. MHC-I-pos tumor cells were surrounded by CD4 and CD8 T cells and M1 macrophages, whereas MHC-I-neg tumor cells were closer to other MHC-I-neg tumor cells. These findings suggest that TME-based classification incorporating tumor cell MHC-I status may improve individualized immunotherapy selection.

cancer biology↗
bioRxiv2026

Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis

Cell-cell interactions shape the fate of mutant cells during cancer initiation but how these interactions evolve during progression to pathologically recognizable lesions remain poorly understood. Here, we investigated cell-cell communication during serous endometrial carcinoma (SEC; also known as uterine serous carcinoma) development using a lineage-traceable mouse model and cross-species analyses of the mouse and human neoplastic endometrium. In mice, the early, pre-dysplastic stage was marked by a global decrease in inferred cell-cell interactions, followed by extensive communication network rewiring during neoplastic progression. Pathway-specific analysis revealed a similar pattern for NOTCH signaling, with NOTCH2 emerging as the dominant NOTCH receptor in Trp53/Rb1-mutant immature epithelial cells. Functionally, NOTCH2 promoted the outgrowth of more proliferative mutant organoids. Cross-species transcriptomic analysis identified conserved immature epithelial states in mouse and human neoplastic endometrial epithelium. In human tissues, NOTCH2 was overexpressed in serous endometrial intraepithelial carcinoma, a precursor of SEC, and in overt SEC. Furthermore, elevated NOTCH2 expression was associated with poor patient survival. These findings link cell-cell communication rewiring during experimental SEC development to conserved neoplastic epithelial states and identify NOTCH2 as an early marker and a potential target of disease interception.

cancer biology↗