
FABP4在腫瘤相關巨噬細胞中介導不飽和脂肪酸誘導的脂肪積累和脂肪分解,從而促進乳腺癌轉移。


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A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo . Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

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Highlights 

1.  Unlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages.

2.  Unsaturated fatty acids activate the FABP4/CEBPα axis for neutral lipid biosynthesis in macrophages

3.  Deficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophages

4.  FABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis

### Competing Interest Statement

The authors have declared no competing interest.

 [1]: pending:yes

FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis

不飽和脂肪酸誘導的fabp4介導的脂肪積累和脂肪分解在腫瘤相關巨噬細胞中促進乳腺癌轉移


不飽和脂肪酸誘導的FABP4介導的脂肪積累和脂肪分解在腫瘤相關巨噬細胞中促進乳腺癌轉移


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HSPA2在二細胞期呈現不對稱表達,調控CARM1及H3R26me2修飾,從而影響內細胞團的命運決定。


The first cell-fate decision is the process by which cells of an embryo take on distinct lineage identities for the first time, thus representing the beginning of developmental patterning. Here, we demonstrate that the molecular chaperone heat shock protein A2 (HSPA2), a member of the 70 kDa heat shock protein (HSP70) family, is asymmetrically expressed in the late 2-cell stage of mouse embryos. The knockdown of Hspa2 in one of the two-cell blastomeres prevented its progeny predominantly toward the inner cell mass (ICM) fate, thus indicating that the differential distribution of HSPA2 in the blastomeres of two-cell embryos can influence the selection of embryonic cell lineages. In contrast, the overexpression of Hspa2 in one of the two-cell blastomeres did not induce blastomeres to differentiate towards the ICM fate. Furthermore, we demonstrated that HSPA2 forms a complex with CARM1 and activates ICM-specific gene expression. Collectively, our results identify HSPA2 as a critical regulator of the first cell-fate decision which specifies the ICM via the execution of commitment and differentiation phases.

### Competing Interest Statement

The authors have declared no competing interest.

The asymmetric expression of HSPA2 in blastomeres governs the first embryonic cell-fate decision

滋養層和內細胞團的第一個細胞命運決定由hspa2的不對稱表達調控


滋養層和內細胞團的第一個細胞命運決定由HSPA2的不對稱表達調控



組織壞死後,遠離損傷部位的細胞會啟動一種稱為「壞死誘導性凋亡」(NiA)的過程,這種過程對於再生至關重要,但其機制尚未完全了解。


Tissue necrosis is a devastating complication for many human diseases and injuries. Unfortunately, our understanding of necrosis and how it impacts surrounding healthy tissue – an essential consideration when developing methods to treat such injuries – has been limited by a lack of robust genetically tractable models. Our lab previously established a method to study necrosis-induced regeneration in the Drosophila wing imaginal disc, which revealed a unique phenomenon whereby cells at a distance from the injury upregulate caspase activity in a process called Necrosis-induced Apoptosis (NiA) that is vital for regeneration. Here we have further investigated this phenomenon, showing that NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge. Furthermore, we find that a proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration. This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism. These data reveal a new means by which non-apoptotic Dronc signaling promotes regenerative proliferation in response to necrotic damage.

### Competing Interest Statement

The authors have declared no competing interest.

Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity

組織壞死後再生由非凋亡性的半胱天冬酶活性介導


不同種類的結腸腺癌細胞顯示其細胞質分配的波動程度存在明顯差異,這可以通過其細胞大小的不對稱分裂來解釋。


人類結腸癌細胞中不對稱分裂的可靠評估


細胞間黏附強度的增加會導致組織從液態轉變為固態,與頂點模型和沃羅諾伊模型的預測相反。這一結果與體外實驗和體內形態發生過程的觀察一致。


細胞間黏附在調節組織流動性中的作用


細胞內膜結構,如高爾基體,在持續的運輸小泡進出過程中,能夠維持其複雜多樣的形態,這是由於非平衡的裂解和融合過程所驅動的。


活躍的細胞內器官形態動力學在運輸通路中的作用


FipA是一種新的FlhF互作蛋白,在細菌極性鞭毛形成中扮演重要角色。FipA與FlhF的相互作用有助於將FlhF定位到細胞極性,並促進鞭毛的合成。


The coordination of cell cycle progression and flagellar synthesis is a complex process in motile bacteria. In γ-proteobacteria, the localization of the flagellum to the cell pole is mediated by the SRP-type GTPase FlhF. However, the mechanism of action of FlhF, and its relationship with the cell pole landmark protein HubP remain unclear. In this study, we discovered a novel protein called FipA that is required for normal FlhF activity and function in polar flagellar synthesis. We demonstrated that membrane-localized FipA interacts with FlhF and is required for normal flagellar synthesis in Vibrio parahaemolyticus , Pseudomonas putida , and Shewanella putrefaciens , and it does so independently of the polar localization mediated by HubP. FipA exhibits a dynamic localization pattern and is present at the designated pole before flagellar synthesis begins, suggesting its role in licensing flagellar formation. This discovery provides insight into a new pathway for regulating flagellum synthesis and coordinating cellular organization in bacteria that rely on polar flagellation and FlhF-dependent localization.

### Competing Interest Statement

The authors have declared no competing interest.

A conserved cell-pole determinant organizes proper polar flagellum formation

保護細胞極性決定因子組織適當的極性鞭毛形成


內在吞噬作用不能有效地將異三聚體 G 蛋白載入到新形成的內吞小泡上，導致 G 蛋白在內體膜上的含量遠低於細胞膜。


Classical G protein-coupled receptor (GPCR) signaling takes place in response to extracellular stimuli and involves receptors and heterotrimeric G proteins located at the plasma membrane. It has recently been established that GPCR signaling can also take place from intracellular membrane compartments, including endosomes that contain internalized receptors and ligands. While the mechanisms of GPCR endocytosis are well understood, it is not clear how well internalized receptors are supplied with G proteins. To address this gap we use gene editing, confocal microscopy, and bioluminescence resonance energy transfer to study the distribution and trafficking of endogenous G proteins. We show here that constitutive endocytosis is sufficient to supply newly internalized endocytic vesicles with 20-30% of the G protein density found at the plasma membrane. We find that G proteins are present on early, late, and recycling endosomes, are abundant on lysosomes, but are virtually undetectable on the endoplasmic reticulum, mitochondria, and the medial Golgi apparatus. Receptor activation does not change heterotrimer abundance on endosomes. Our findings provide a subcellular map of endogenous G protein distribution, suggest that G proteins may be partially excluded from nascent endocytic vesicles, and are likely to have implications for GPCR signaling from endosomes and other intracellular compartments.

### Competing Interest Statement

The authors have declared no competing interest.

Visualization of endogenous G proteins on endosomes and other organelles

內在吞噬作用效率低下限制異三聚體-g-蛋白在內體上的含量


內在吞噬作用效率低下限制異三聚體 G 蛋白在內體上的含量



滑胚細胞極性化的時間差異影響其後的細胞命運指定,早期極性化的細胞更易產生外胚層細胞。


The first lineage allocation in mouse and human embryos separates the inner cell mass (ICM) from the outer trophectoderm (TE). This symmetry breaking event is executed through polarization of cells at the 8-cell stage and subsequent asymmetric divisions, generating polar (TE) and apolar (ICM) cells. Here, we show that embryo polarization is unexpectedly asynchronous. Cells polarizing at the early and late 8-cell stage have distinct molecular and morphological properties that direct their following lineage specification, with early polarizing cells being biased towards producing the TE lineage. More recent studies have also implicated heterogeneities between cells prior to the 8-cell stage in the first lineage allocation: cells exhibiting reduced methyltransferase CARM1 activity at the 4-cell stage are predisposed towards the TE fate. Here, we demonstrate that reduced CARM1 activity and upregulation of its substrate BAF155 promote early polarization and TE specification. These findings provide a link between asymmetries at the 4-cell stage and polarization at the 8-cell stage, mechanisms of the first lineage allocation that had been considered separate.

### Competing Interest Statement

The authors have declared no competing interest.

Asynchronous mouse embryo polarization leads to heterogeneity in cell fate specification

滑胚細胞極性化的非同步性導致細胞命運指定的異質性


糖酵解通量的提高可以促進視網膜前驅細胞向視杆細胞的分化,這是通過激活Wnt信號通路實現的。


Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggestive of a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In an RPC-specific conditional knock-out of Phosphatase and tensin homolog ( Pten- cKO) and in an RPC-specific conditional gain-of-function of dominant active PFKB3 (cyto PFKB3 ), glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment maturation. Conversely, glycolytic inhibition in retinal explants, achieved either with 2-deoxy-d-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+ symporters, which lowers intracellular pH, suppresses RPC proliferation and photoreceptor differentiation. Mechanistically, we show that Wnt signaling, the top-upregulated pathway in Pten- cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling using a Ctnnb1- cKO phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation and outer segment maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.

IMPACT STATEMENT Transgenic and pharmacological approaches reveal developmental elevations in glycolytic flux have an instructive role in promoting rod photoreceptor differentiation and maturation via activation of Wnt signaling.

### Competing Interest Statement

The authors have declared no competing interest.

Glycolytic flux controls retinal progenitor cell differentiation via regulating Wnt signaling

提高糖酵解通量控制視網膜前驅細胞分化的機制是通過調節wnt信號


提高糖酵解通量控制視網膜前驅細胞分化的機制是通過調節Wnt信號
