Biology subjects

Fioravanti, C.

Publications and source records attributed to Fioravanti, C..

3 recordsLinked to original sources

bioRxiv2026

KRAS-Mediated CCDC6 Degradation Drives xCT Upregulation and Ferroptosis Evasion

Oncogenic KRAS mutations drive tumorigenesis by promoting pro-survival signaling and metabolic reprogramming, including the maintenance of redox balance to evade oxidative stress. A key mechanism involves the upregulation of the xCT cystine/glutamate antiporter, which sustains glutathione (GSH) synthesis and protects cells from oxidative damage and ferroptosis. While it is known that the ETS1-ATF4 complex mediates transcriptional upregulation of xCT, the upstream regulators linking KRAS signaling to this axis remain to be fully defined. Here, we demonstrate that oncogenic KRAS signaling induces the GSK3{beta}-mediated proteasomal degradation of the tumor suppressor CCDC6. We show that CCDC6 acts as a negative regulator of the xCT-promoting transcription factor ATF4 by directly interacting with it and preventing its recruitment to the xCT promoter. Consequently, KRAS-driven CCDC6 degradation disinhibits ATF4, leading to increased xCT expression, elevated intracellular GSH, and enhanced resistance to ferroptosis. Crucially, pharmacological inhibition of CCDC6 turnover using proteasome, GSK3{beta}, or specific KRAS mutant inhibitors (Sotorasib, Adagrasib, HRS4642) restored CCDC6 protein levels and robustly sensitized KRAS-mutated cells to ferroptosis-inducing agents like Sulfasalazine. Furthermore, validation in preclinical models and human colorectal cancer samples revealed that CCDC6 protein levels are predominantly downregulated in KRAS-mutant cases This work uncovers a novel KRAS/CCDC6/xCT signaling axis that mediates ferroptosis resistance in KRAS-mutated cancers. Moreover, it identifies CCDC6 turnover as a critical vulnerability and a promising therapeutic target to enhance the efficacy of ferroptosis-inducing agents.

cancer biology↗

bioRxiv2021

A new adaptive procedure for estimating perceptual thresholds: the effects of observer bias and its correction.

Adaptive threshold estimation procedures sample close to a subjects perceptual threshold by dynamically adapting the stimulation based on the subjects performance. Yet, perceptual thresholds not only depend on the observers sensory capabilities but also on any bias in terms of their expectations and response preferences, thus distorting the precision of the threshold estimates. Using the framework of signal detection theory (SDT), independent estimates of both, an observers sensitivity and internal processing bias can be delineated from threshold estimates. While this approach is commonly available for estimation procedures engaging the method of constant stimuli (MCS), correction procedures for adaptive methods (AM) are only scarcely applied. In this article, we introduce a new AM that takes individual biases into account, and that allows for a bias-corrected assessment of subjects sensitivity. This novel AM is validated with simulations and compared to a typical MCS-procedure, for which the implementation of bias correction has been previously demonstrated. Comparing AM and MCS demonstrates the viability of the presented AM. Besides its feasibility, the results of the simulation reveal both, advantages, and limitations of the proposed AM. The procedure has considerable practical implications, in particular for the design of shaping procedures in sensory training experiments, in which task difficulty has to be constantly adapted to an observers performance, to improve training efficiency.

neuroscience↗

bioRxiv2018

Functional dynamics underlying near-threshold perception of facial emotions: a magnetoencephalography investigation.

Conscious perception of emotional valence of faces has been proposed to involve top-down and bottom-up information processing. Yet, the underlying neuronal mechanisms of these two processes and the implementation of their cooperation is still unclear. We hypothesized that the networks activated during the interaction of top-down and bottom-up processes are the key substrates responsible for perception. We assessed the participation of neural networks involved in conscious perception of emotional stimuli near the perceptual threshold using a visual-backward-masking paradigm in 12 healthy individuals using magnetoencephalography. Providing visual stimulation near the perceptual threshold enabled us to compare correctly and incorrectly recognized facial emotions and assess differences in top-down modulation for these stimuli using coherence analysis. We found a fronto-parietal network oscillating in the lower gamma band and exerting top-down control as determined by the causality measure of phase slope index. We demonstrated that correct recognition of facial emotions involved high-beta and low-gamma activity in parietal networks, Incorrect recognition was associated with enhanced coupling in the gamma band between left frontal and right parietal regions. Our results indicate that fronto-parietal control of the perception of emotional face stimuli relies on the right-hemispheric dominance of synchronized gamma band activity.

neuroscience↗