Elaimy AL, Mercurio AM. Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology. Sci Signal. 2018 Oct 16. PMID: 30327408
OUR PAPER ON α6β4-PROMOTED FERROPTOSIS RESISTANCE IN MATRIX-DETACHED CELLS IS PUBLISHED IN JBC!
Abstract
Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of lipid-targeting reactive oxygen species that kill cells by damaging their plasma membrane. The lipid repair enzyme GSH peroxidase 4 (GPX4) protects against this oxidative damage and enables cells to resist ferroptosis. Recent work has revealed that matrix-detached carcinoma cells can be susceptible to ferroptosis and that they can evade this fate through the signaling properties of the α6β4 integrin, which sustains GPX4 expression. Although these findings on ferroptosis are provocative, they differ from those in previous studies indicating that matrix-detached cells are prone to apoptosis via a process referred to as anoikis. In an effort to reconcile these discrepant findings, here we observed that matrix-detached epithelial and carcinoma cells cluster spontaneously via a mechanism that involves the cell adhesion protein PVRL4 (also known as Nectin-4). We found that this clustering process allows these cells to survive by stimulating a PVRL4/α6β4/Src signaling axis that sustains GPX4 expression and buffers against lipid peroxidation. In the absence of α6β4, PVRL4-mediated clustering induced an increase in lipid peroxidation that was sufficient for triggering ferroptosis. When the clustering was inhibited, single cells did not exhibit a significant increase in lipid peroxidation in the absence of α6β4, and they were more susceptible to apoptosis than to ferroptosis. These results indicate that ferroptosis induction depends on cell clustering in matrix-detached cells that lack α6β4 and imply that the fate of matrix-detached cells can be determined by the state of their cell-cell interactions.
Brown CW, Amante JJ, Mercurio AM. Cell clustering mediated by the adhesion protein PVRL4 is necessary for α6β4 integrin-promoted ferroptosis resistance in matrix-detached cells. J Biol Chem. 2018 Aug 17. PMID: 29934307
SANJOY'S PAPER ON IMP3 STABILIZATION OF WNT5B mRNA FACILIATING TAZ ACTIVATION IN BREAST CANCER IS OUT IN CELL REPORTS!
Abstract
Insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with many aggressive cancers and implicated in the function of breast cancer stem cells (CSCs). The mechanisms involved, however, are poorly understood. We observed that IMP3 facilitates the activation of TAZ, a transcriptional co-activator of Hippo signaling that is necessary for the function of breast CSCs. The mechanism by which IMP3 activates TAZ involves both mRNA stability and transcriptional regulation. IMP3 stabilizes the mRNA of an alternative WNT ligand (WNT5B) indirectly by repressing miR145-5p, which targets WNT5B, resulting in TAZ activation by alternative WNT signaling. IMP3 also facilitates the transcription of SLUG, which is necessary for TAZ nuclear localization and activation, by a mechanism that is also mediated by WNT5B. These results demonstrate that TAZ can be regulated by an mRNA-binding protein and that this regulation involves the integration of Hippo and alternative WNT-signaling pathways.
Samanta S, Guru S, Elaimy AL, Amante JJ, Ou J, Yu J, Zhu LJ, Mercurio AM. MP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer. Cell Rep. 2018 May 29. PMID: 29847788
AMEER'S PAPER ON VEGF-NEUROPILIN-2 SIGNALING PROMOTING STEM-LIKE TRAITS IN BREAST CANCER CELLS IS PUBLISHED IN SCIENCE SIGNALING!
Abstract
The role of vascular endothelial growth factor (VEGF) signaling in cancer is not only well known in the context of angiogenesis but also important in the functional regulation of tumor cells. Autocrine VEGF signaling mediated by its co-receptors called neuropilins (NRPs) appears to be essential for sustaining the proliferation and survival of cancer stem cells (CSCs), which are implicated in mediating tumor growth, progression, and drug resistance. Therefore, understanding the mechanisms involved in VEGF-mediated support of CSCs is critical to successfully treating cancer patients. The expression of the Hippo effector TAZ is associated with breast CSCs and confers stem cell-like properties. We found that VEGF-NRP2 signaling contributed to the activation of TAZ in various breast cancer cells, which mediated a positive feedback loop that promoted mammosphere formation. VEGF-NRP2 signaling activated the GTPase Rac1, which inhibited the Hippo kinase LATS, thus leading to TAZ activity. In a complex with the transcription factor TEAD, TAZ then bound and repressed the promoter of the gene encoding the Rac GTPase-activating protein (Rac GAP) β2-chimaerin. By activating GTP hydrolysis, Rac GAPs effectively turn off Rac signaling; hence, the TAZ-mediated repression of β2-chimaerin resulted in sustained Rac1 activity in CSCs. Depletion of β2-chimaerin in non-CSCs increased Rac1 activity, TAZ abundance, and mammosphere formation. Analysis of a breast cancer patient database revealed an inverse correlation between β2-chimaerin and TAZ expression in tumors. Our findings highlight an unexpected role for β2-chimaerin in a feed-forward loop of TAZ activation and the acquisition of CSC properties.
Elaimy AL, Guru S, Chang C, Ou J, Amante JJ, Zhu LJ, Goel HL, Mercurio AM. VEGF-neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP β2-chimaerin. Sci Signal. 2018 May 1. PMID: 29717062
ARTHUR MERCURIO PRESENTS AT THE NORRIS COTTON CANCER CENTER AT DARTMOUTH-HITCHCOCK MEDICAL CENTER.
Art presented a short talk at the Norris Cotton Cancer Center Grand Rounds titled, 'Mechanisms that Regulate Cancer Stem Cell Fate and Tumor Plasticity', hosted by the Dartmouth-Hitchcock Medical Center.
A recording of Art's presentation can be found below:
