Cancer research最新文献

Emerging evidence suggests that TGFβ1 can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the antiangiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiologic angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the antiangiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating antiangiogenic factor thrombospondin 1 (TSP1) in endothelial cells (EC) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced miR145 expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma displayed increased miR145 and decreased SMAD3 and TSP1 compared with ECs from adjacent nontumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in hepatocellular carcinoma tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis. Significance: Suppression of angiogenesis by TGFβ1 is mediated by TSP1 upregulation in endothelial cells and abrogated by HIF1α-miR145 activity in the hypoxic tumor microenvironment, providing potential targets to remodel the tumor vasculature.

Therapy-exposed surviving cancer cells may have encountered profound epigenetic remodeling that renders these drug-tolerant persisters candidate drivers of particularly aggressive relapses. Typically presenting as slow-to-nongrowing cells, persisters are senescent or senescence-like cells. In this issue of Cancer Research, Ramponi and colleagues study mTOR/PI3K inhibitor-induced embryonic diapause-like arrest (DLA) as a model of persistence in lung cancer and melanoma cells and compare this persister condition with therapy-induced senescence in the same cells. The DLA phenotype recapitulated some but not all features attributed to senescent cells, lacking, for instance, an inflammatory secretome otherwise known as the senescence-associated secretory phenotype. A CRISPR dropout screen pointed to methyl group-providing one-carbon metabolism and further to H4K20me3-mediated repression of senescence-associated secretory phenotype-related IFN response genes selectively in DLA-like persister cells. Conversely, inhibition of H4K20-active KMT5B/C methyltransferases derepressed inflammatory programs and was toxic in DLA cells. These findings not only suggest exploitable vulnerabilities of DLA-like persister cells but also unveil general technical and conceptual challenges of cultured multipassage cell line-based persister studies. Collectively, the approach chosen and insights obtained will stimulate a productive scientific debate on senescence-like features and their reversibility across drug-tolerant persister cells. See related article by Ramponi et al., p. 32.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as a super enhancer-associated gene in human PDAC, which encodes the flavin monooxygenase MICAL2 that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 impacts PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention.