
FABP4は、不飽和脂肪酸によるマクロファージの脂肪蓄積と利用を促進し、乳がんの転移に寄与する。


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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

脂肪酸結合タンパク質4-fabp4-が腫瘍関連マクロファージの脂肪蓄積とリポリシスを促進し-乳がんの転移を促進する


脂肪酸結合タンパク質4(FABP4)が腫瘍関連マクロファージの脂肪蓄積とリポリシスを促進し、乳がんの転移を促進する


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メラノーマ細胞の存在によりケラチノサイトがEMT様の変化を示し、これがメラノーマの浸潤を抑制する。


Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an Epithelial–Mesenchymal Transition (EMT)-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b-jam3b and pgrn-sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment (TME) may limit melanoma invasion through altered cell-cell interactions.

### Competing Interest Statement

RMW is a paid consultant to N-of-One, a subsidiary of Qiagen. There is no conflict with the work described in this manuscript.

Restraint of melanoma progression by cells in the local skin environment

メラノーマ進行の抑制における局所皮膚環境の細胞の役割


PA2γはC1QBPと相互作用し、その安定性を高めることで、酸化的リン酸化機能を亢進させ、口腔扁平上皮癌の悪性進行を促進する。


Proteasome activator 28γ (PA28γ) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as main research model, we discovered that PA28γ interacted with complement 1q binding protein (C1QBP), which is dependent on the N-terminus of C1QBP rather than the known functional domain (amino acids 168-213). Notably, we found that PA28γ can enhance C1QBP protein stability in OSCC. Functionally, PA28γ contributes to the malignant progression of OSCC by affecting mitochondrial morphology and oxidative phosphorylation (OXPHOS) through C1QBP in vitro and vivo. Mechanically, PA28γ upregulate the expression of optic atrophy 1 (OPA1), mitofusin 2 (MFN1), mitofusin 2 (MFN2) and the mitochondrial respiratory complex by C1QBP. Moreover, in a clinical cohort of OSCC patients, PA28γ was positively correlated with C1QBP expression and negatively correlated with prognosis. Therefore, C1QBP is also a potential target for the treatment and prognosis of cancer.

### Competing Interest Statement

The authors have declared no competing interest.

PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP

口腔扁平上皮癌の悪性進行を促進するpa2γによるc1qbpを介した酸化的リン酸化機能の亢進


口腔扁平上皮癌の悪性進行を促進するPA2γによるC1QBPを介した酸化的リン酸化機能の亢進



壊死後の組織再生には、損傷部位から離れた細胞におけるカスパーゼ活性化が重要な役割を果たす。一部のこれらの細胞は、アポトーシスを免れて生き残り、後期の再生増殖を促進する。


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

壊死後の組織再生は非アポトーシス性カスパーゼ活性によって仲介される


コロン癌細胞の細胞質分配には大きな揺らぎがあり、これは細胞サイズの非対称分裂に起因することが明らかになった。


コロン癌細胞における非対称分裂の頑健な評価


細胞間接着の強さが組織の物性と形態を決定する重要な要因である。接着が増加すると組織は固体化し、一方で接着が減少すると組織は流動化する。


細胞間接着が組織の流動性を調節する役割


細胞分裂による等容積分割を伴う能動的物質系では、細胞間相互作用と細胞分裂の相互作用により、長期的に自己相似的な複雑な集団運動が生み出される。


細胞分裂による等容積分割を伴う能動的物質の複雑な動力学


細胞内小器官の膜動態は、小胞の分裂と融合による非平衡駆動力によって生み出され、維持される。この非平衡ダイナミクスにより、小器官の形態変化や能動的な移動が引き起こされる。


活性膜動態学-細胞内小器官の輸送経路における動態


活性膜動態学:細胞内小器官の輸送経路における動態



細胞膜の高い水透過性により、マクロ分子凝縮による細胞内浸透圧緩衝は不可能である。


[Watson et al . (2023][1], Macromolecular condensation buffers intracellular water potential, Nature 623: 842-852) have proposed that the reversible formation and disassembly of molecular condensates could act as the primary buffer of cytoplasmic osmolality in the face of changes in extracellular osmolality. In this communication, I show using well-established membrane biophysics, that the water permeability of plasma membranes is likely to overwhelm any cytoplasmic water buffers.

### Competing Interest Statement

The authors have declared no competing interest.

 [1]: #ref-27

Macromolecular condensation is unlikely to buffer intracellular osmolality

細胞内浸透圧を緩衝するマクロ分子凝縮は不可能である


内在化の過程でヘテロ三量体G蛋白質は細胞膜と比べて低密度になる。受容体活性化によってもこの傾向は変わらない。


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

内在化の非効率性により-ヘテロ三量体g蛋白質の細胞内小器官での存在量が制限される


内在化の非効率性により、ヘテロ三量体G蛋白質の細胞内小器官での存在量が制限される
