0000000000116440
AUTHOR
Stefano Piccolo
A Mutually Stimulating Loop Involving Emx2 and Canonical Wnt Signalling Specifically Promotes Expansion of Occipital Cortex and Hippocampus
The correct size of the different areas composing the mature cerebral cortex depends on the proper early allocation of cortical progenitors to their distinctive areal fates, as well as on appropriate subsequent tuning of their area-specific proliferation--differentiation profiles. Whereas much is known about the genetics of the former process, the molecular mechanisms regulating proliferation and differentiation rates within distinctive cortical proto-areas are still largely obscure. Here we show that a mutual stimulating loop, involving Emx2 and canonical Wnt signalling, specifically promotes expansion of the occipito-hippocampal anlage. Collapse of this loop occurring in Emx2 2/2 mutants …
Abstract CT261: METAMECH -A Master Observational Trial empowering mechanobiology translational research and mechanobased proof of concept trials in breast cancer
Abstract Background: Breast cancer (BC) is the most frequent tumor in women worldwide. BC lethality is caused by aggressive, therapy-resistant metastases (mBC). Preliminary data have shown that mBC lesions are invariably embedded into a densely packed network of fibrous extracellular matrix, making the metastatic microenvironment a potent inducer of mechanical inputs, ultimately leading to the activation of the transcription factors YAP/TAZ. Aberrant mechano-signaling could thus represent a vulnerability of metastasis, which can be exploited to develop new therapeutic strategies. To investigate how metastatic outgrowth is regulated by the physical properties of the microenvironment, and how…
YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING
Ageing is intimately connected to the induction of cell senescence(1,2), but why this is so remains poorly understood. A key challenge isthe identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing(3). Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the e…
TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells
Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs…
Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ
Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human t…