KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer.

KRAS G12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRAS G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS G12C -driven PDAC model. Compared to the classical KRAS G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'do-not-eat-me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS G12D -driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. Significance: Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS G12C inhibitor in PDAC. We generated an autochthonous KRAS G12C -driven PDAC model, which revealed allele-specific biology of the KRAS G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRAS G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.

Study on controllable preparation of high performance andradite based glass-ceramics by harmful iron-rich waste slag.

Due to containing abundant FeOx and trace heavy metals (Pb, As, Cr, Cd, etc.), the disposal of lead/zinc smelting slag (LSS-ZSS) with ultra-high historical reserves has attracted increased attention. Using LSS-ZSS to prepare glass-ceramics is a good method to solve the problem of LSS-ZSS accumulation and realize heavy metal solidification, whereas there are some technical challenges that are difficult to deal with. A large amount of FeOx component in LSS-ZSS would not only lead to melt overflow, but also cause early crystallization of basic glass. In this work, through the directional modification of LSS-ZSS and the subsequent crystallization kinetics regulation, we successfully prepare high performance glass-ceramics with andradite and hematite as the main crystal phases. In addition, by means of SEM, PXRD, FTIR spectra and XPS, the morphology/phase transformation, fine structure and valence variations of iron components in LSS-ZSS at different temperature zones are systematically studied. The maximum shrinkage rate of resultant basic glasses is 27 %, and the maximum flexural strength and compressive strength of glass-ceramics are 128 MPa and 890 MPa, respectively. This work would not only benefit to solve the problem of resource utilization of harmful LSS-ZSS, but also provide a possible reference for the utilization of iron-rich waste slag in magnetic properties related fields.

Author Correction: CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.