Liver cancer heterogeneity modeled by in situ genome editing of hepatocytes

Abstract

Mechanistic study and precision treatment of primary liver cancer (PLC) are hindered by marked heterogeneity, which is challenging to recapitulate in any given liver cancer mouse model. Here, we report the generation of 25 mouse models of PLC by in situ genome editing of hepatocytes recapitulating 25 single or combinations of human cancer driver genes. These mouse tumors represent major histopathological types of human PLCs and could be divided into three human-matched molecular subtypes based on transcriptomic and proteomic profiles. Phenotypical characterization identified subtype- or genotype-specific alterations in immune microenvironment, metabolic reprogramming, cell proliferation, and expression of drug targets. Furthermore, single-cell analysis and expression tracing revealed spatial and temporal dynamics in expression of pyruvate kinase M2 ( Pkm2 ). Tumor-specific knockdown of Pkm2 by multiplexed genome editing reversed the Warburg effect and suppressed tumorigenesis in a genotype-specific manner. Our study provides mouse PLC models with defined genetic drivers and characterized phenotypical heterogeneity suitable for mechanistic investigation and preclinical testing.

Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment

“…The concept of tumor heterogeneity leading to a low immune response to tumors is important in clinical evaluation [ 259 ]. Intertumor or intratumor heterogeneity is thought to be an impediment to tumor targeted therapy [ 260 ]. Tumor heterogeneity and cancer stem cell plasticity are linked, and it is thought to be an emerging marker related to cancer invasion [ 261 ].…”

Prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma

“…Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major subtypes of primary liver cancers (PLCs) [ 1 ]. The HCC accounts for up to 85%, while the ICC accounts for 10 to 15% of all PLC cases [ 2 ]. Although some early-stage PLC patients can benefit from surgical treatment and systematic anti-tumor therapies, including target therapy and immunotherapy, those with advanced stage can only receive limited benefits from few multi-kinase inhibitors [ 2 , 3 ].…”

“…The HCC accounts for up to 85%, while the ICC accounts for 10 to 15% of all PLC cases [ 2 ]. Although some early-stage PLC patients can benefit from surgical treatment and systematic anti-tumor therapies, including target therapy and immunotherapy, those with advanced stage can only receive limited benefits from few multi-kinase inhibitors [ 2 , 3 ]. Currently, immunotherapeutic strategies, such as tumor vaccines, adoptive T-cell transfer therapy, immune-checkpoint inhibitors, and even immunotherapeutic strategies combined with conventional strategies, have been increasingly investigated in managing HCC and ICC.…”

Remarkably High Conductivity and Power Factor in D–D′‐type Thermoelectric Polymers Based on Indacenodithiophene

“…[ 3,8–14 ] Owing to the low κ of organic TE materials and the difficulty to measure correctly, the power factor (PF = α 2 σ) is often used to evaluate their TE performance. [ 9,15–18 ] Recently, extensive studies on TE material design, fundamentals in charge generation/transport, and optimization of device architectures have been performed, successfully demonstrating a record high ZT up to 0.75 for poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/ionic liquid (IL) heterostructures. [ 19 ] The enhancement of ZT is attributed to only a slight drop in σ and a significant rise in α due to ion accumulation of IL on the polymer surface which can scatter the low energy charge carriers and thus increase the mean energy of the holes at the cold side of the PEDOT:PSS films.…”