The activation and differentiation of cancer-associated fibroblasts (CAF) are involved in tumor progression. Here, we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE2) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE2 signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation. CAF proliferation upon EP3 inhibition required p38 MAPK signaling. Mechanistically, TGFβ–activated kinase-like protein (TAK1L), which was identified as a negative regulator of p38 MAPK activation, was decreased following ablation of mPGES-1 or EP3. In contrast with its effects on primary tumor growth, disruption of PGE2 signaling in CAFs induced epithelial-to-mesenchymal transition in cancer organoids and promoted metastasis in mice. Moreover, TAK1L expression in CAFs was associated with decreased CAF activation, reduced metastasis, and prolonged survival in human breast cancer. These data characterize a new pathway of regulating inflammatory CAF activation, which affects breast cancer progression. Significance: The inflammatory lipid prostaglandin E2 suppresses cancer-associated fibroblast expansion and activation to limit primary mammary tumor growth while promoting metastasis.

The heart continually senses and responds to mechanical stimuli that balance cardiac structure and activity. Tensile forces, compressive forces, and shear stress are sensed by the different cardiac cell types and converted into signals instructing proper heart morphogenesis, postnatal growth, and function. Defects in mechanotransduction, the ability of cells to convert mechanical stimuli into biochemical signals, are implicated in cardiovascular disease development and progression. In this review, we summarize the current knowledge on how mechanical forces are transduced to chromatin through the tensed actomyosin cytoskeleton, the linker of nucleoskeleton and cytoskeleton (LINC) complex and the nuclear lamina. We also discuss the functional significance of the LINC complex in cardiovascular disease.

Organisms respond to stressors through a coordinated set of physiological and behavioural responses. Zebrafish provides an opportunity to study conserved mechanisms underlying the stress-response that is regulated largely by the neuroendocrine Hypothalamus-Pituitary-Adrenal/Interrenal (HPA) axis, with glucocorticoids (GC) as the final effector. In this study, we evaluated the effect of chronically active GC signalling in early life on the baseline and stress evoked GC(cortisol) levels in larval zebrafish. To this end, we employed an optogenetic actuator, Beggiatoa photoactivated adenylyl cyclase, expressed in the interrenal cells of zebrafish and demonstrate that its chronic activation leads to hypercortisolaemia and dampens the acute-stress evoked cortisol levels, across a variety of stressor modalities during early life. This blunting of stress-response, a phenotype reported by many studies to be observed in human subjects exposed to early-life trauma, was conserved in ontogeny at a later developmental stage. Furthermore, we observe a strong reduction of proopiomelanocortin (POMC)-expressing cells in the pituitary as well as global upregulation of FKBP5 gene expression, impinging on the negative feedback regulation elicited by elevated cortisol levels. Going forward, we propose that this model can be leveraged to tease apart the mechanisms underlying developmental programming of HPA axis by early-life stress and its implications for vulnerability and resilience to stress in adulthood.