RESUMEN

Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor organoids are generated to explore heterogeneity and evolution via single-cell RNA sequencing. HCC272 with high status of epithelia-mesenchymal transition proves broad-spectrum drug resistance. By examining the expression pattern of cancer stem cells markers (e.g., PROM1, CD44, and EPCAM), it is found that CD44 positive population may render drug resistance in HCC272. UMAP and pseudo-time analysis identify the intratumoral heterogeneity and distinct evolutionary trajectories, of which catenin beta-1 (CTNNB1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and nuclear paraspeckle assembly transcript 1 (NEAT1) advantage expression clusters are commonly shared across hepatobiliary organoids. CellphoneDB analysis further implies that metabolism advantage organoids with enrichment of hypoxia signal upregulate NEAT1 expression in CD44 subgroup and mediate drug resistance that relies on Jak-STAT pathway. Moreover, metabolism advantage clusters shared in several organoids have similar characteristic genes (GAPDH, NDRG1 (N-Myc downstream regulated 1), ALDOA, and CA9). The combination of GAPDH and NDRG1 is an independent risk factor and predictor for patient survival. This study delineates heterogeneity of hepatobiliary tumor organoids and proposes that the collaboration of intratumoral heterogenic subpopulations renders malignant phenotypes and drug resistance.

Asunto(s)

Enfermedades del Sistema Digestivo/genética , Neoplasias Gastrointestinales/genética , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/genética , ARN Largo no Codificante/genética , beta Catenina/genética , Antígenos de Neoplasias/genética , Anhidrasa Carbónica IX/genética , Proteínas de Ciclo Celular/genética , Enfermedades del Sistema Digestivo/tratamiento farmacológico , Enfermedades del Sistema Digestivo/patología , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Fructosa-Bifosfato Aldolasa/genética , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Receptores de Hialuranos/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Quinasas Janus/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Organoides/efectos de los fármacos , Organoides/metabolismo , Organoides/patología , RNA-Seq , Factores de Transcripción STAT/genética , Análisis de la Célula Individual , Transcriptoma/genética

RESUMEN

Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma (HCC). Its application has changed the status of sorafenib as the only first-line TKI treatment for HCC for more than a decade. Evidence has shown that lenvatinib possesses antitumor proliferation and immunomodulatory activity in preclinical studies. In comparison, lenvatinib was non-inferior to sorafenib in overall survival (OS), and even shows superiority with regard to all the secondary efficacy endpoints. Immune-checkpoint inhibitors(ICIs)are now being incorporated into HCC treatment. Positive outcomes have been achieved in the combination of lenvatinib plus ICIs, bringing broader prospects for HCC. This review presents an overview on the therapeutic mechanisms and clinical efficacy of lenvatinib in HCC, and we discuss the future perspectives of lenvatinib in HCC management with focus on biomarker-guided precision medicine.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Hepatocelular/metabolismo , Humanos , Inmunomodulación , Inmunoterapia , Neoplasias Hepáticas/metabolismo , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos

RESUMEN

Temperature-programmed desorption (TPD) is one of the most straightforward surface science experiments for the determination of the thermodynamic and kinetic parameters of a reaction. In our previous study (J. Phys. Chem. C, 2013, 117, 6136-6142), we proposed a model combining DFT methods with microkinetics to investigate the TPD spectra of NH3 and H2O on the RuO2(110) surface. Although our model predicted both the physisorption and chemisorption peaks of both adsorbates in agreement with the experimental TPD spectra, it failed to explain the region between the physisorption and chemisorption areas and underestimated the intensity of the adsorbate in these areas. Hence, to improve our model, in this study, we considered the diffusion of adsorbates from the sub-monolayer to the second layer. Accordingly, we simulated the TPD spectra of both NH3 and H2O on the RuO2(110) surface using condensation approximation. Our results indicate that the diffusion barriers of the adsorbates at high coverage are smaller than their direct desorption energies. Hence, the diffusion of the adsorbates to the second layer from the sub-monolayer at higher coverage is kinetically favorable, which then desorb directly even at low temperatures. Furthermore, the simulated TPD spectra clearly depict the previous experimental results of both adsorbates after considering the diffusion.