The bone microenvironment invigorates metastatic seeds for further dissemination.

Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.

Characterization of Cancer Evolution Landscape Based on Accurate Detection of Somatic Mutations in Single Tumor Cells.

Accurate detection of somatic mutations in single tumor cells is greatly desired as it allows us to quantify the single-cell mutation burden and construct the mutation-based phylogenetic tree. Here we developed scNanoSeq chemistry and profiled 842 single cells from 21 human breast cancer samples. The majority of the mutation-based phylogenetic trees comprise a characteristic stem evolution followed by the clonal sweep. We observed the subtype-dependent lengths in the stem evolution. To explain this phenomenon, we propose that the differences are related to different reprogramming required for different subtypes of breast cancer. Furthermore, we reason that the time that the tumor-initiating cell took to acquire the critical clonal-sweep-initiating mutation by random chance set the time limit for the reprogramming process. We refer to this model as a reprogramming and critical mutation co-timing (RCMC) subtype model. Next, in the sweeping clone, we observed that tumor cells undergo a branched evolution with rapidly decreasing selection. In the most recent clades, effectively neutral evolution has been reached, resulting in a substantially large number of mutational heterogeneities. Integrative analysis with 522-713X ultra-deep bulk whole genome sequencing (WGS) further validated this evolution mode. Mutation-based phylogenetic trees also allow us to identify the early branched cells in a few samples, whose phylogenetic trees support the gradual evolution of copy number variations (CNVs). Overall, the development of scNanoSeq allows us to unveil novel insights into breast cancer evolution.

Droplet-based transcriptome profiling of individual synapses.

Synapses are crucial structures that mediate signal transmission between neurons in complex neural circuits and display considerable morphological and electrophysiological heterogeneity. So far we still lack a high-throughput method to profile the molecular heterogeneity among individual synapses. In the present study, we develop a droplet-based single-cell (sc) total-RNA-sequencing platform, called Multiple-Annealing-and-Tailing-based Quantitative scRNA-seq in Droplets, for transcriptome profiling of individual neurites, primarily composed of synaptosomes. In the synaptosome transcriptome, or 'synaptome', profiling of both mouse and human brain samples, we detect subclusters among synaptosomes that are associated with neuronal subtypes and characterize the landscape of transcript splicing that occurs within synapses. We extend synaptome profiling to synaptopathy in an Alzheimer's disease (AD) mouse model and discover AD-associated synaptic gene expression changes that cannot be detected by single-nucleus transcriptome profiling. Overall, our results show that this platform provides a high-throughput, single-synaptosome transcriptome profiling tool that will facilitate future discoveries in neuroscience.

Ultrastable, Deformable, and Stretchable Luminescent Organic-Inorganic Perovskite Nanocrystal-Polymer Composites for 3D Printing and White Light-Emitting Diodes.

Organic-inorganic perovskite nanocrystals with excellent optoelectronic properties have been utilized in various applications, despite their stability issues. The perovskite materials are sensitive to environments such as polar solvents, moisture, and heat. Thus, they are not used for extrusion three-dimensional (3D) printing, as it is usually conducted in the ambient environment and requires heating to liquefy the printed materials. In this work, 11 thermoplastic polymers conventionally used for extrusion 3D printing were investigated to test their capability as protective encapsulation materials for perovskite nanocrystals. Three of them exhibited good protective properties, and one (polycaprolactone, PCL) of these three could be blended with perovskite nanocrystals to form perovskite nanocrystal-PCL composites, which were deformable and stretchable once heated. Because of the low melting point of PCL, the perovskite nanocrystals maintained their optical properties after 3D printing, and the printed objects were still having fluorescent behavior. Moreover, fluorescent micrometer-sized fibers based on the perovskite nanocrystal-PCL composites could also be simply prepared using cotton candy makers. Perovskite nanocrystal-PCL composite films with different emission wavelengths were incorporated with blue light-emitting diodes (LEDs) to realize white LEDs with Commission Internationale de l'Éclairage chromaticity coordinates of (0.33, 0.33).

Leakage-free solution-processed organic light-emitting diode using a ternary host with single-diode emission area up to 6 × 11.5 cm2.

The electrical current leakage and stability are studied for solution-processed OLEDs with areas of 4.45 mm2, 3 × 3.2 cm2, and 6 × 11.5 cm2. The emission layer of the OLED has a ternary or binary mixed host with hole-transporting molecules tris(4-carbazoyl-9-ylphenyl)amine (TCTA) and 9-(4-tert-butylphenyl)-3,6-bis(triphenylsilyl)-9H-carbazole (CzSi), together with the electron-transporting molecule 2,7-bis(diphenylphosphoryl)-9,9'-spirobi[fluorene] (SPPO13). The phosphorescent emitters are Ir(mppy)3 for green and bis[4-(4-tert-butylphenyl)thieno[3,2-c]pyridine][N,N'-diisopropylbenamidinato]iridium(iii) (PR-02) for orange. Poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-(4,4'-(N-(4-sec-butylphenyl))diphenylamine)] (TFB) is used as the hole transport layer and PEDOT:PSS is used as the hole injection layer. On top of the emission layer, CsF/Al is deposited by thermal evaporation as the cathode. All organic layers are deposited by blade coating and the initial current leaking defects can be avoided by careful control of the coating conditions. The detrimental burning point caused by a local current short developed after long-time operation can be avoided by reducing the operation voltage using a ternary mixed host. The operation voltage is only 4 V at 100 cd m-2 and 5 V at 250 cd m-2 for the green emitting device. Furthermore, the crystallization defect is reduced by the ternary host. For the orange emitting device, the binary host is good enough with an operating voltage of 5 V at 100 cd m-2. For an area as large as 6 × 11.5 cm2, the OLED shows good stability and there is no burning point after an operation of over 1600 hours.

All-Solution-Processed Red and Orange-Red Organic Light-Emitting Diodes with High-Efficiencies: The Effect of Mixed-Host Emissive Layers and Thermal Annealing Treatment.

The instability of the organic light-emitting diodes (OLEDs) during operation can be attributed to the existence of point defects on the organic layers. In this work, the effect of mixed-host emissive layer and the thermal annealing treatment were investigated to eliminate defects and to boost the device performance. The mixed-host system includes 4,4',4''-tri (9-carbazoyl) triphenylamine (TCTA) and 2,7-bis(diphenylphosphoryl)-9, 9'-spirobi[fluorene] (SPPO13). The mixed-host emissive layer with thermal annealing treatment showed low roughness and few pinholes, and the devices fabricated from this emissive layer exhibited high efficiencies, high stabilities, and long lifetimes. The red and orange-red OLEDs exhibited efficiencies of 13.9 cd/A and 24.35 cd/A, respectively. The longest half-lifetime (L0 =500 cd/m2 ) of the red and orange-red OLEDs were 158 h and 180 h, respectively. Efforts were made to solve problems in large-area coating and to reduce the number of defects on in organic layer. Large-active-area (active area=3 cm×4 cm) red phosphorescent OLEDs (PhOLEDs) devices were realized with very high current efficiency up to 9 cd/A.