Necroptosis microenvironment directs lineage commitment in liver cancer

Seehawer, Marco; Heinzmann, Florian; D’Artista, Luana; Harbig, Jule; Roux, Pierre-François; Hoenicke, Lisa; Dang, Hien; Klotz, Sabrina; Robinson, Lucas; Dore, Gregory J.; Rozenblum, Nir; Kang, Tae‐Won; Chawla, Rishabh; Buch, Thorsten; Vucur, Mihael; Roth, Mareike; Zuber, Johannes; Luedde, Tom; Sipos, Bence; Longerich, Thomas; Heikenwälder, Mathias; Wang, Xin Wei; Bischof, Oliver; Zender, Lars

doi:10.1038/s41586-018-0519-y

Cited by 299 publications

(251 citation statements)

References 42 publications

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“…This would suggest that MLKL-dependent necroptosis, eventually through a pathway independent of RIPK3, would protect OTULIN deficient hepatocytes from death by apoptosis. Interestingly, a recent study demonstrated that suppression of necroptosis in hepatocytes could promote hepatocyte apoptosis favoring the development of HCC (Seehawer et al, 2018). This observation suggested that hepatocyte necroptosis generates a liver cytokine microenvironment which promotes the development of intrahepatic cholangiocarcinoma and not HCC from oncogenically transformed hepatic cells (Seehawer et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Verboom

Martens

Priem

et al. 2019

Preprint

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Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of inflammatory pathologies. OTULIN is a deubiquitinating enzyme that specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC), and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. OTULIN was shown to negatively control NF-κB signaling in response to various stimuli, but also to protect cells from tumor necrosis factor (TNF)-induced apoptosis. To investigate the importance of OTULIN in liver homeostasis and pathology, we developed a novel mouse line specifically lacking OTULIN in liver parenchymal cells. These mice spontaneously develop a severe liver disease, characterized by liver inflammation, hepatocyte apoptosis and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues the severe liver pathology, and knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects from developing liver disease, demonstrating that death receptor-mediated apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease pathogenesis in hepatocyte-specific OTULIN deficient mice. Together, our study reveals the critical importance of OTULIN in protecting hepatocytes from death, and thereby avoid development of chronic liver inflammation and HCC in mice.

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Section: Discussionmentioning

confidence: 99%

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Verboom

Martens

Priem

et al. 2019

Preprint

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“…A recent study on mice addressed how a hepatic microenvironment, created by two different methods of oncogenic delivery, could influence the type of hepatic tumor [109]. The authors showed that the same oncogenic drivers delivered to mature hepatocytes gave rise to iCCA when embedded in a necroptosis-dominated microenvironment, while an apoptotic milieu favored the development of HCC [40,109]. The necroptosis microenvironment was characterized by specific inflammatory cytokines (e.g., C-C motif ligand 6) secreted from immune cells, which were, in turn, activated by DAMPs released from necroptotically dying hepatocytes [18,40,59].…”

Section: Necroptosis and Cholangiocarcinomamentioning

confidence: 99%

Necroptosis in Cholangiocarcinoma

Sarcognato

Jong

Fabris

et al. 2020

Cells

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Necroptosis is a type of regulated cell death that is increasingly being recognized as a relevant pathway in different pathological conditions. Necroptosis can occur in response to multiple stimuli, is triggered by the activation of death receptors, and is regulated by receptor-interacting protein kinases 1 and 3 and mixed-lineage kinase domain-like, which form a regulatory complex called the necrosome. Accumulating evidence suggests that necroptosis plays a complex role in cancer, which is likely context-dependent and can vary among different types of neoplasms. Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis and, as a pro-inflammatory death type, it may inhibit tumor progression by releasing damage-associated molecular patterns to elicit robust cross-priming of anti-tumor CD8+ T cells. The development of therapeutic strategies triggering necroptosis shows great potential for anti-cancer therapy. In this review, we summarize the current knowledge on necroptosis and its role in liver biliary neoplasms, underlying the potential of targeting necroptosis components for cancer treatment.Cells 2020, 9, 982 2 of 18 (RIPK3) and mixed lineage kinase domain-like (MLKL) [4]. Therefore, necroptosis is an alternative mode of CD when the caspase-8-dependent apoptotic pathway is blocked. It is now well-established that various stimuli can initiate necroptosis, including intra-and extracellular factors, such as tumor necrosis factor α (TNFα) and reactive oxygen species (ROS) [5].A hallmark of cancer is the ability of malignant cells to evade apoptosis. Therefore, the induction of necroptosis could be an alternative strategy for killing cancer cells. Several therapeutics able to affect the necroptotic cascade have recently been developed, and a few of them are already in phase 1 trials for the treatment of inflammatory diseases. Moreover, necroptosis modulation is becoming the target of several new anti-cancer strategies. In fact, it has been demonstrated that apoptosis-resistant tumors respond to necroptosis, and that necroptosis can create an immunogenic microenvironment that enhances tumor clearance [6]. These aspects will be further discussed in the following chapters.Herein, we will discuss the general aspects of necroptosis and what is currently known on its involvement in cholangiocarcinoma (CCA), in order to provide perspectives for future studies in this relatively new field. Overview on Types of Cell DeathIn 2005, the Nomenclature Committee on Cell Death (NCCD) defined the first CD classification purely based on morphological criteria. This classification included three major forms of CD: types I, II, and III [7]. Type I CD, termed apoptosis, exhibits cell shrinkage, membrane blebbing, DNA fragmentation, chromatin condensation, and the formation of apoptotic bodies. Apoptosis is a form of RCD and responds to two different death signals: damage from inside the cell, such as DNA damage, which elicits an intrinsic pathway, and extracellular stimuli, such as TNFα and the Fas ligand, ...

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“…(1) The regulatory molecules and tissue context that commit transformed hepatic cells toward HCC or CCA are still largely unknown, but a recent mouse study showed that hepatocytes with aberrantly activated oncogenes give rise to CCA when embedded in a necroptosis-dominated hepatic microenvironment. (65) DAMPs released by necroptotic hepatocytes can activate immune cells to secrete various specific cytokines to form a robust inflammatory environment, determining the outgrowth of CCA from transformed hepatocytes. In contrast, hepatocytes that harbor the same oncogenic driver will give rise to HCC if it is not adjacent to necroptotic hepatocytes.…”

Section: Liver Cancermentioning

confidence: 99%

Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

et al. 2019

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Cell death is a natural process for the turnover of aged cells, but it can also arise as a result of pathological conditions. Cell death is recognized as a key feature in both acute and chronic hepatobiliary diseases caused by drug, alcohol, and fat uptake; by viral infection; or after surgical intervention. In the case of chronic disease, cell death can lead to (chronic) secondary inflammation, cirrhosis, and the progression to liver cancer. In liver transplantation, graft preservation and ischemia/reperfusion injury are associated with acute cell death. In both cases, so‐called programmed cell death modalities are involved. Several distinct types of programmed cell death have been described of which apoptosis and necroptosis are the most well known. Parenchymal liver cells, including hepatocytes and cholangiocytes, are susceptible to both apoptosis and necroptosis, which are triggered by distinct signal transduction pathways. Apoptosis is dependent on a proteolytic cascade of caspase enzymes, whereas necroptosis induction is caspase‐independent. Moreover, different from the “silent” apoptotic cell death, necroptosis can cause a secondary inflammatory cascade, so‐called necroinflammation, triggered by the release of various damage‐associated molecular patterns (DAMPs). These DAMPs activate the innate immune system, leading to both local and systemic inflammatory responses, which can even cause remote organ failure. Therapeutic targeting of necroptosis by pharmacological inhibitors, such as necrostatin‐1, shows variable effects in different disease models.

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Necroptosis microenvironment directs lineage commitment in liver cancer

Cited by 299 publications

References 42 publications

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Necroptosis in Cholangiocarcinoma

Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

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