Biology subjects

Di Tullio, F.

Publications and source records attributed to Di Tullio, F..

3 recordsLinked to original sources

bioRxiv2025

Liver Zonation Disruption Fuels Hepatocellular Carcinoma in Chronic Liver Disease

Hepatocellular carcinoma (HCC) arises almost exclusively in chronic liver disease (CLD), yet the classical etiological drivers of injury insufficiently explain why only a subset of patients progress to cancer. Here, we identify disruption of liver metabolic zonation, specifically, aberrant expansion of {beta}-catenin activity from pericentral to periportal territories as a previously unrecognized tumorigenic risk state that emerges across etiologically diverse CLDs. Using spatial transcriptomics and immunohistochemistry from murine liver disease followed by human sample validation, we demonstrate that MASLD/MASH, alcohol-associated hepatitis, viral hepatitis, and immune-mediated cholangiopathies share a striking periportal induction of pericentral {beta}-catenin target programs, indicating a conserved zonation disturbance independent of disease etiology. Since {beta}-catenin expansion occurs alongside inflammation, fibrosis, and metabolic dysfunction in human CLD, its direct oncogenic contribution remained unclear. To functionally isolate the tumorigenic consequence of zonation disruption itself from these confounding disease processes, we employed hepatocyte-specific deletion of ZNRF3 and RNF43--negative regulators that physiologically restrict {beta}-catenin to the pericentral zone. Lineage tracing demonstrates that ZNRF3/RNF43 deletion drives selective periportal hepatocyte proliferation, zonal reprogramming, and tumor initiation in a {beta}-catenin-dependent manner, establishing zonation disruption as a direct mechanistic driver of carcinogenesis. The resulting tumors exhibit a distinct metabolic and immunologic phenotype, including heightened mitochondrial respiration, preserved periportal identity, and T-cell competence, and correspond to a molecularly defined subset comprising 5-10% of human HCCs. Together, these findings reveal {beta}-catenin zonation expansion as a conserved and previously unrecognized HCC risk factor that mechanistically links chronic liver injury to malignant transformation. They further establish ZNRF3/RNF43 deletion as a tractable model of zonation-driven hepatocarcinogenesis and identify a distinct human HCC subtype with unique therapeutic vulnerabilities, opening new avenues for mechanism-based risk stratification, early detection and preventive therapeutic strategies in patients with chronic liver disease.

cancer biology↗

bioRxiv2025

Targeting ZNRF3 and RNF43 to Restore Regeneration and Reverse Metabolic Dysfunction-Associated Steatotic Liver Disease

Liver regeneration and hepatocyte metabolic identity are disrupted in metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms of restore liver regeneration and reprogram metabolism for disease reversal remains poorly understood. Here, we show that {beta}-Catenin activity progressively declines in hepatocytes during MASH in both humans and mice, coinciding with impaired regeneration and defective lipid clearance. Targeted deletion of the endogenous WNT pathway inhibitors ZNRF3 and RNF43 in hepatocytes after MASH onset reactivates {beta}-Catenin signaling, leading to robust regression of steatosis, inflammation, and fibrosis, and restoring regenerative capacity across multiple fatty liver disease models. Mechanistically, this therapeutic effect is driven by {beta}-Catenin-dependent induction of the alternative bile acid synthesis pathway without disrupting systemic lipid homeostasis. Importantly, both short-and long-term deletion of ZNRF3/RNF43 restores liver function without triggering tumorigenesis or hepatotoxicity, indicating a safe therapeutic window. These findings reveal that physiological activation of WNT/{beta}-catenin signaling via ZNRF3 and RNF43 offers a viable regenerative and metabolic strategy for reversing fatty liver disease.

cell biology↗

bioRxiv2023

A Mutation-driven oncofetal regression fuels phenotypic plasticity in colorectal cancer

Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment1. However, the molecular mechanisms underlying resistance to LGR5+ CSCs depletion in colorectal cancer (CRC)2,3 remain largely elusive. Here, we unveil the existence of a primitive cell state dubbed the oncofetal (OnF) state, which works in tandem with the LGR5+ stem cells (SCs) to fuel tumor evolution in CRC. OnF cells emerge early during intestinal tumorigenesis and exhibit features of lineage plasticity. Normally suppressed by the Retinoid X Receptor (RXR) in mature SCs, the OnF program is triggered by genetic deletion of the gatekeeper APC. We demonstrate that diminished RXR activity unlocks an epigenetic circuity governed by the cooperative action of YAP and AP1, leading to OnF reprogramming. This high-plasticity state is inherently resistant to conventional chemotherapies and its adoption by LGR5+ CSCs enables them to enter a drug-tolerant state. Furthermore, through phenotypic tracing and ablation experiments, we uncover a functional redundancy between the OnF and stem cell (SC) states and show that targeting both cellular states is essential for sustained tumor regression in vivo. Collectively, these findings establish a mechanistic foundation for developing effective combination therapies with enduring impact on CRC treatment.

cancer biology↗