Hao Gu

Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we develop a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic PIK3CA mutation, Trp53 loss, and MYC overexpression. Using this model together with human EC cell lines, patient-derived organoids (PDOs), xenografts, and patient datasets, we investigate mechanisms underlying resistance to PI3Kα-targeted therapy. Single-cell profiling reveals that FGFR1/2 upregulation associates with intrinsic resistance, whereas FGFR3 characterizes acquired resistance. Dual FGFR and PI3Kα inhibition produces superior tumor control compared with either agent alone. Mechanistically, FGFR signaling promotes immune evasion by downregulating MHC-I/HLA-mediated antigen presentation and enriching M2-type tumor-associated macrophages. FGFR inhibition reverses these changes and synergizes with anti-PD-1 therapy to enhance antitumor immune responses and establish durable immune memory. Collectively, these findings identify FGFR signaling as a key driver of therapeutic resistance and immune escape in SEC and support FGFR-targeted combination strategies.

Loss of the tumor suppressor PTEN is strongly associated with a lack of response to immune checkpoint blockade therapies in cancer patients, but the underlying mechanisms are not fully understood. We have developed a transformation model where knocking out PTEN in human mammary epithelial cells drives dependence on the p110β subunit of PI3K and, notably, elicits a robust induction of endogenous retroviral elements (ERVs) and activation of interferon signaling. This constitutive cell-intrinsic interferon response, hallmarked by hyperactivated STAT1, is also observed in human tumors with a PTEN-low status. We further found that PTEN deficiency renders cancer cells resistant to the cytotoxic effects of immune cells and interferon-γ. Notably, PTEN loss also results in a dependency on an activated DNA damage response pathway, leading to an exquisite vulnerability to CDK12 inhibition. Our study suggests an interferon adaptation model in which tumors driven by PTEN deficiency inherently activate the interferon response, enabling them to adapt to interferon cytotoxicity and gain resistance to immunotherapies.

Multimodal emotion recognition is an important research topic in artificial intelligence. However, due to problems such as complex environments and inaccurate annotations, current systems are hard to meet the demands of practical applications. Therefore, we organize the MER series of competitions to promote the development of this field. Last year, we launched MER2023, focusing on three interesting topics: multi-label learning, noise robustness, and semi-supervised learning. In this year's MER2024, besides expanding the dataset size, we further introduce a new track around open-vocabulary emotion recognition. The main purpose of this track is that existing datasets usually fix the label space and use majority voting to enhance the annotator consistency. However, this process may lead to inaccurate annotations, such as ignoring non-majority or non-candidate labels. In this track, we encourage participants to generate any number of labels in any category, aiming to describe emotional states as accurately as possible. Our baseline code relies on MERTools and is available at: https://github.com/zeroQiaoba/MERTools/tree/master/MER2024.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

B cell acute lymphoid leukemia uses the mitochondrial respiration as the main energy source that enhances drug resistance.

Background: Epithelial cells produce cytokines that promote lung inflammation, which involves a mechanism of oxidative stress. Oligomeric proanthocyanidin (OPC) presents benefits on several respiratory disorders but little is known on asthma. Aims and Objectives: To investigate the impact of OPC on the regulation of epithelial phenotypes and airway microenvironment. Methods: A total of 34 mild stable asthma patients with conventionally budesonide/formoterol inhalated were randomly divided into placebo, low-, and high-dose OPC groups. HBEs were used and TNF-α was chosen to establish an inflammatory cellular model. Results: High-dose OPC notably improved the FEV1% and ACT scores in asthma patients. The serum levels of IgE, TNF-α, IL-4 and IL-13 were significantly decreased. The numbers of peripheral eosinophils in OPC groups markedly declined in a time-dose dependent manner. In vitro OPC decreased the secretion of diverse pro-inflammatory cytokines closely implicated in asthma such as eotaxin-1. These effects might be probably due to the inhibition of intracellular phosphorylation of MAPK, highlighting an essential link between ROS and MAPK. Additionally, OPC was given to OVA-sensitized mice and attenuated airway hyperresponsiveness (OVA + OPC vs. OVA, RI: 3.39 ± 0.32 vs. 4.92 ± 0.37 cmH2O/ml/s, P<0.05), inflammation and remodeling, encompassing a phenotypic alteration of epithelial cells. OPC rebalanced the airway microenvironment (IgE, TNF-α, IL-4 and IL-13) in murine asthmatic airways along with a suppression of malondialdehyde. Conclusion: The illumination of the impacts of OPC on asthma may offer prospective clinical therapeutic benefits of anti-oxidation.

The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We generated a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and demonstrate that there are 3 distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells had an enhanced level of mitochondrial respiration but a glycolytic level similar to that of SoNar-high cells. Interestingly, 10% of SoNar-low cells were enriched for 65% of total immunophenotypic fetal liver HSCs (FL-HSCs) and contained approximately fivefold more functional HSCs than their SoNar-high counterparts. SoNar was able to monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivated MDH1 to sustain the malate-aspartate NADH shuttle activity and HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for metabolic studies of HSCs or other types of stem cells.

One of the bottlenecks of the treatments for malignant hematopoietic disorders is the unavailability of sufficient amount of hematopoietic stem cells (HSCs). HSCs are considered to be originated from the aorta-gonad-mesonephros and gradually migrates into fetal liver and resides in a unique microenvironment/niche of bone marrow. Although many intrinsic and extrinsic factors (niche components) are reported to be involved in the origination, maturation, migration, and localization of HSCs at different developmental stages, the detailed molecular mechanisms still remain largely unknown. Previous studies have shown that intrinsic metabolic networks may be critical for the cell fate determinations of HSCs. For example, HSCs mainly utilize glycolysis as the main energy sources; oxidative phosphorylation is required for the homeostasis of HSCs; lipid or amino acid metabolisms may also sustain HSC stemness. Mechanistically, lots of regulatory pathways, such as MEIS1/HIF1A and PI3K/AKT/mTOR signaling, are found to fine-tune the different nutrient metabolisms and cell fate commitments of HSCs. However, more efforts are required for the optimization and establishment of precise metabolic techniques specific for the HSCs with relatively rare cell frequency and understanding of the basic metabolic properties and their underlying regulatory mechanisms of different nutrients (such as glucose) during the different developmental stages of HSCs.