Targeting intratumor heterogeneity suppresses colorectal cancer chemoresistance and metastasis.

Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.

Preparation and Physicochemical Analysis of Camellia sinensis cv. 'Ziyan' Anthocyanin Microcapsules.

The new tea cultivar Ziyan has a high content of anthocyanin and ester catechins in the raw material, but the conventional processing and application methods are limited. To explore its application potential, the freeze-drying method was used to prepare microcapsules with an embedding time of 30 min, solid content of 30%, and core to wall ratio of 1:10 (g/g). The anthocyanin recovery was 95.94 ± 0.50%, and the encapsulation efficiency was 96.15 ± 0.11%. The stability of microcapsules and composite wall materials was evaluated in the simulation system. Results showed that microcapsules employing a maltodextrin-gum arabic ratio of 2:8 (w/w) as the wall material significantly reduced degradation rates, extending anthocyanin half-life under various storage conditions. Characterization indicated improved physical properties of Ziyan anthocyanin powder post-microencapsulation. FT-IR and DSC- revealed the formation of a new phase between anthocyanins and wall materials, leading to increased enthalpy and enhanced thermal stability. The microencapsulation results of this experiment proved that the storage stability of anthocyanin was effectively enhanced.

Cascaded p-d Orbital Hybridization Interaction in Ultrathin High-Entropy Alloy Nanowires Boosts Complete Non-CO Pathway of Methanol Oxidation Reaction.

Designing high efficiency platinum (Pt)-based catalysts for methanol oxidation reaction (MOR) with high "non-CO" pathway selectivity is strongly desired and remains a grand challenge. Herein, PtRuNiCoFeGaPbW HEA ultrathin nanowires (HEA-8 UNWs) are synthesized, featuring unique cascaded p-d orbital hybridization interaction by inducing dual p-block metals (Ga and Pb). In comparison with Pt/C, HEA-8 UNWs exhibit 15.0- and 4.2-times promotion of specific and mass activity for MOR. More importantly, electrochemical in situ FITR spectroscopy reveals that the production/adsorption of CO (CO*) intermediate is effectively avoided on HEA-8 UNWs, leading to the complete "non-CO" pathway for MOR. Theoretical calculations demonstrate the optimized electronic structure of HEA-8 UNWs can facilitates a lower energy barrier for the "non-CO" pathway in the MOR.

CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer.

CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits ß-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated ß-catenin translocation inactivates Wnt(Wingless and INT-1)/ß-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/ß-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.