0000000000179113
AUTHOR
Silvio Bicciato
MYC-driven epigenetic reprogramming favors the onset of tumorigensis by inducing a stem cell-like state
AbstractBreast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes resulted difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Over-expression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathw…
Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome
TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading …
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…
PO-298 MYC favours the onset of tumour initiating cells by inducing epigenetic reprogramming of mammary epithelial cells towards a stem cell-like state
ABSTRACT Introduction Breast cancer consists of highly heterogenous tumours whose cell of origin resulted difficult to be defined. Recent findings highlighted the possibility that tumor-initiating cells (TICs) may arise from dedifferentiation of lineage-committed cells, by reactivation of multipotency in response to oncogenic insults. MYC is the most frequently amplified oncogene in breast cancer and the activation of MYC pathway has been associated with the basal-like subtype, which is characterised by poor survival and lack of a specific therapeutic strategy. Although MYC has been considered a driver oncogene in breast cancer, its mechanism of action in tumour initiation has been poorly a…
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…
Artificial Intelligence for Hospital Health Care:Application Cases and Answers to Challenges in European Hospitals
The development and implementation of artificial intelligence (AI) applications in health care contexts is a concurrent research and management question. Especially for hospitals, the expectations regarding improved efficiency and effectiveness by the introduction of novel AI applications are huge. However, experiences with real-life AI use cases are still scarce. As a first step towards structuring and comparing such experiences, this paper is presenting a comparative approach from nine European hospitals and eleven different use cases with possible application areas and benefits of hospital AI technologies. This is structured as a current review and opinion article from a diverse range of…
MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state
Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermo…
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…