Biomarkers for response to immunotherapy in hepatobiliary malignancies.

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic options of hepatobiliary malignancies. However, the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies. The identification of reliable predictors of the response to immunotherapy is urgently needed. DATA SOURCES: Literature search was conducted in PubMed for relevant articles published up to May 2022. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS: Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence. Tumor programmed death-ligand 1 (PD-L1) expression is the most widely studied biomarker in hepatocellular carcinoma (HCC) and biliary tract cancers (BTCs), but there are conflicting results on its predictive potential. Tumor mutational burden (TMB) is generally low both in HCC and BTCs, and the clinical trials of TMB are rare in hepatobiliary malignancies. Promisingly, mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H) may be a predictive biomarker of response to anti-PD-1 therapy in BTCs. Furthermore, some emerging biomarkers, such as gut microbiota, show predictive potential in the preliminary studies. Radiomics and liquid-biopsy biomarkers, including circulating tumor cells, circulating tumor DNA (ctDNA) and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response, showing a new promising direction. CONCLUSIONS: Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic. Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies. The identification of predictors for response to ICIs is an urgent need and major challenge. Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.

Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma.

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.

S100 calcium-binding protein A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma.

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.

Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response.

BACKGROUND: The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. METHODS: The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays. RESULTS: NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. CONCLUSIONS: NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.

MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming.

BACKGROUND: Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear. METHODS: The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo. RESULTS: Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1. CONCLUSIONS: Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.

ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition.

Metabolic reprogramming plays an important role in supporting tumor growth. However, little is known about the metabolic alterations that promote cancer metastasis. In this study, we identify acyl-CoA thioesterase 12 (ACOT12) as a key player in hepatocellular carcinoma (HCC) metastasis. The expression of ACOT12 is significantly down-regulated in HCC tissues and is closely associated with HCC metastasis and poor survival of HCC patients. Gain- and loss-of-function studies demonstrate that ACOT12 suppresses HCC metastasis both in vitro and in vivo. Further mechanistic studies reveal that ACOT12 regulates the cellular acetyl-CoA levels and histone acetylation in HCC cells and that down-regulation of ACOT12 promotes HCC metastasis by epigenetically inducing TWIST2 expression and the promotion of epithelial-mesenchymal transition. Taken together, our findings link the alteration of acetyl-CoA with HCC metastasis and imply that ACOT12 could be a prognostic marker and a potential therapeutic target for combating HCC metastasis.