Chencheng Han

Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.

Cancer-associated fibroblasts (CAFs) are the key component of tumor stromal. High heterogeneity of CAFs reflects in their origin, phenotype and function. Biological function which can be suggested by biomarkers of distinct CAF subgroups may be different, even opposite, just like water and fire. Identifying CAF subpopulations expressing different biomarkers and reconciling the relationship of the "water and fire" among distinct CAF subsets may be a breakthrough in tumor therapy. Herein, we briefly summarize the biomarkers commonly used or newly identified for distinct CAFs in terms of their features and potential clinical benefits.

BACKGROUND: Besides featured glucose consumption, recent studies reveal that cancer cells might prefer "addicting" specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear. METHODS: Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved. RESULTS: We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD. CONCLUSION: Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.

In this Letter, we report the dark matter search results from the commissioning run (Run0) and the first science run (Run1) of the PandaX-4T experiment. The two datasets were processed with a unified procedure, with the Run1 data treated blindly. The data processing is improved compared to previous work, unifying the low-level signal reconstruction in a wide energy range up to 120 keV. With a total exposure of 1.54 tonne·year, no significant excess of nuclear recoil events is found. The lowest 90% confidence level exclusion on the spin-independent cross section is 1.6×10^{-47} cm^{2} at a dark matter mass of 40 GeV/c^{2}. Our results represent the most stringent constraint for a dark matter mass above 100 GeV/c^{2}.

The PandaX-4T liquid xenon detector at the China Jinping Underground Laboratory is used to measure the solar ^{8}B neutrino flux by detecting neutrinos through coherent scattering with xenon nuclei. Data samples requiring the coincidence of scintillation and ionization signals (paired), as well as unpaired ionization-only signals (US2), are selected with energy threshold of approximately 1.1 keV (0.33 keV) nuclear recoil energy. Combining the commissioning run and the first science run of PandaX-4T, a total exposure of 1.20 and 1.04 tonne·year are collected for the paired and US2, respectively. After unblinding, 3 and 332 events are observed with an expectation of 2.8±0.5 and 251±32 background events, for the paired and US2 data, respectively. A combined analysis yields a best-fit ^{8}B neutrino signal of 3.5 (75) events from the paired (US2) data sample, with ∼37% uncertainty, and the background-only hypothesis is disfavored at 2.64σ significance. This gives a solar ^{8}B neutrino flux of (8.4±3.1)×10^{6} cm^{-2} s^{-1}, consistent with the standard solar model prediction. It is also the first indication of solar ^{8}B neutrino "fog" in a dark matter direct detection experiment.