PARP-1 selectively impairs KRAS-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma.

OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined. DESIGN: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular features of Kras-driven and Kras-wildtype iCCA. Clinical implications were confirmed in authentic human iCCA. RESULTS: PARP-1 was significantly enhanced in KRAS-mutant human iCCA. PARP-1-based interventions preferentially impaired cell viability and tumourigenicity in human KRAS-mutant cell lines. Consistently, loss of Parp-1 provoked distinct phenotype in Kras/Tp53-induced versus Akt/Nicd-induced iCCA and abolished Kras-dependent cholangiocarcinogenesis. Transcriptome analyses confirmed preferential impairment of DNA damage response pathways and replicative stress response mediated by CHK1. Consistently, inhibition of CHK1 effectively reversed PARP-1 mediated effects. Finally, Parp-1 depletion induced molecular switch of KRAS-mutant iCCA recapitulating good prognostic human iCCA patients. CONCLUSION: Our findings identify the novel prognostic and therapeutic role of PARP-1 in iCCA patients with activation of oncogenic KRAS signalling.

Heterogeneity in Liver Cancer Immune Microenvironment: Emerging Single-Cell and Spatial Perspectives.

Primary liver cancer is a solid malignancy with a high mortality rate. The success of immunotherapy has shown great promise in improving patient care and highlights a crucial need to understand the complexity of the liver tumor immune microenvironment (TIME). Recent advances in single-cell and spatial omics technologies, coupled with the development of systems biology approaches, are rapidly transforming the landscape of tumor immunology. Here we review the cellular landscape of liver TIME from single-cell and spatial perspectives. We also discuss the cellular interaction networks within the tumor cell community in regulating immune responses. We further highlight the challenges and opportunities with implications for biomarker discovery, patient stratification, and combination immunotherapies.

Single-Cell Characterization of the Tumor Ecosystem in Liver Cancer.

Tumor heterogeneity along with the complex landscape of the tumor microenvironment create critical challenges for effective liver cancer interventions. Characterizing the tumor ecosystem at the single-cell level may provide insight into the collective behaviors of tumor cells and their interplays with stromal and immune cells. Here we introduce the experimental protocol and computational methods for the single-cell study of liver cancer, which may be essential for a mechanistic understanding of the tumor ecosystem in liver cancer and further pave the way for developing novel therapeutics.

Phosphate-rich cellulose beads for efficient cesium extraction from aqueous solutions: a novel approach for cellulose utilization.

In this work, phosphate-rich cellulose beads (CBPs) were first used for cesium extraction from aqueous solutions. These green, abundant, cheap, and renewable CBPs demonstrated a high adsorption capacity and fast absorption rate. Besides, the CBPs also exhibited excellent stability and recycling performance, as well as good selectivity. This study presents the promising application potential of cellulose for efficient cesium extraction from aqueous media.

Constructing a Novel Moderately Modulus "Rigid-Flexible" Structure with Synergistic Reinforcement on the Carbon Fiber Surface to Enhance the Mechanical Properties of Carbon Fiber/Epoxy Composites at Elevated Temperatures.

To improve the mechanical performance of carbon fiber (CF)/epoxy composites in high-temperature environments, a moderately modulus gradient modulus interlayer was constructed at the interface phase region of composites. This involved the design of a "rigid-flexible" synergistic reinforcement structure, incorporating rigid nanoparticle GO@CNTs and a flexible polymer polynaphthyl ether nitrile ketone onto the CF surface. Notably, at 180 °C, compared to commercial CF composites, the CF-GO@CNTs-PPENK composites displayed a remarkable improvement in their mechanical characteristics (interfacial shear, interlaminar shear, flexural strength, and modulus), achieving enhancements of 173.0, 91.5, 225.7, and 376.4%, respectively. The principal reason for this the moderately modulus interface phase composed of GO@CNTs-PPENK (where GO and CNTs predominantly consist of carbon atoms with sp2-hybridized orbitals, forming highly stable C-C structures, while PPENK possesses a "twisted non-coplanar" structure), which exhibited resistance to deformation at high temperatures. Moreover, it greatly improved the mechanical interlocking, wettability, and chemical compatibility between CF and the epoxy. It also played a crucial role in balancing and buffering the modulus disparity. The interface failure behavior and reinforcement mechanisms of the CF composites were analyzed. Furthermore, validation of the presence of a moderately modulus gradient interlayer at the interface phase region of CF-GO@CNTs-PPENK composites was performed by using atomic force microscopy. This study has established a theoretical foundation for the development of high-performance CF composites for use in high-temperature fields.

Lineage and ecology define liver tumor evolution in response to treatment.

A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here, we present a single-cell transcriptome-based strategy to determine the evolution of longitudinal tumor biopsies from liver cancer patients by measuring cellular lineage and ecology. We construct a lineage and ecological score as joint dynamics of tumor cells and their microenvironments. Tumors may be classified into four main states in the lineage-ecological space, which are associated with clinical outcomes. Analysis of longitudinal samples reveals the evolutionary trajectory of tumors in response to treatment. We validate the lineage-ecology-based scoring system in predicting clinical outcomes using bulk transcriptomic data of additional cohorts of 716 liver cancer patients. Our study provides a framework for monitoring tumor evolution in response to therapeutic intervention.

Identification of intracellular bacteria from multiple single-cell RNA-seq platforms using CSI-Microbes.

The study of the tumor microbiome has been garnering increased attention. We developed a computational pipeline (CSI-Microbes) for identifying microbial reads from single-cell RNA sequencing (scRNA-seq) data and for analyzing differential abundance of taxa. Using a series of controlled experiments and analyses, we performed the first systematic evaluation of the efficacy of recovering microbial unique molecular identifiers by multiple scRNA-seq technologies, which identified the newer 10x chemistries (3' v3 and 5') as the best suited approach. We analyzed patient esophageal and colorectal carcinomas and found that reads from distinct genera tend to co-occur in the same host cells, testifying to possible intracellular polymicrobial interactions. Microbial reads are disproportionately abundant within myeloid cells that up-regulate proinflammatory cytokines like IL1Β and CXCL8, while infected tumor cells up-regulate antigen processing and presentation pathways. These results show that myeloid cells with bacteria engulfed are a major source of bacterial RNA within the tumor microenvironment (TME) and may inflame the TME and influence immunotherapy response.