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Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.

Maintenance of undifferentiated, long-lived, and often quiescent stem cells in the basal compartment is important for homeostasis and regeneration of multiple epithelial tissues, but the molecular mechanisms that coordinately control basal cell fate and stem cell quiescence are elusive. Here, we report an epithelium-intrinsic requirement for Zeb1, a core transcriptional inducer of epithelial-to-mesenchymal transition, for mammary epithelial ductal side branching and for basal cell regenerative capacity. Our findings uncover an evolutionarily conserved role of Zeb1 in promoting basal cell fate over luminal differentiation. We show that Zeb1 loss results in increased basal cell proliferation at the expense of quiescence and self-renewal. Moreover, Zeb1 cooperates with YAP to activate Axin2 expression, and inhibition of Wnt signaling partially restores stem cell function to Zeb1-deficient basal cells. Thus, Zeb1 is a transcriptional regulator that maintains both basal cell fate and stem cell quiescence, and it functions in part through suppressing Wnt signaling.

Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.

Directional migration is inherently important for epithelial tissue regeneration and repair, but how it is precisely controlled and coordinated with cell proliferation is unclear. Here, we report that Ovol2, a transcriptional repressor that inhibits epithelial-to-mesenchymal transition (EMT), plays a crucial role in adult skin epithelial regeneration and repair. Ovol2-deficient mice show compromised wound healing characterized by aberrant epidermal cell migration and proliferation, as well as delayed anagen progression characterized by defects in hair follicle matrix cell proliferation and subsequent differentiation. Epidermal keratinocytes and bulge hair follicle stem cells (Bu-HFSCs) lacking Ovol2 fail to expand in culture and display molecular alterations consistent with enhanced EMT and reduced proliferation. Live imaging of wound explants and Bu-HFSCs reveals increased migration speed but reduced directionality, and post-mitotic cell cycle arrest. Remarkably, simultaneous deletion of Zeb1 encoding an EMT-promoting factor restores directional migration to Ovol2-deficient Bu-HFSCs. Taken together, our findings highlight the important function of an Ovol2-Zeb1 EMT-regulatory circuit in controlling the directional migration of epithelial stem and progenitor cells to facilitate adult skin epithelial regeneration and repair.

Luteinizing hormone (LH), a heterodimeric glycoprotein produced by pituitary gonadotrope cells, regulates gonadal function. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates LH synthesis and secretion. GnRH induces LHβ subunit (Lhb) expression via the transcription factor, early growth response 1 (EGR1), acting on the Lhb promoter. In contrast, overexpression of zinc finger E-box binding homeobox 1 (ZEB1) represses LH production in mice, but the underlying mechanism was not previously elucidated. Here, we observed that ZEB1 inhibited GnRH-stimulated but not basal Lhb mRNA expression in homologous murine LβT2 cells. Moreover, ZEB1 blocked GnRH and/or EGR1 induction of murine Lhb but not human LHB promoter-reporter activity in these cells. Using chimeric reporters, we mapped the species-specific ZEB1 sensitivity to sequence differences, including in Z- and E-boxes, in the proximal Lhb/LHB promoters, immediately upstream of the transcription start sites. ZEB1 bound to the murine Lhb promoter with higher affinity than to the human LHB promoter in this region. To examine ZEB1's physiological role in LH synthesis, we characterized gonadotrope-specific Zeb1 knockout mice. Loss of ZEB1 in gonadotropes did not affect LH production or secretion. Collectively, the data suggest that ZEB1, when overexpressed, can inhibit GnRH/EGR1 induction of murine Lhb transcription but does not play a necessary role in LH synthesis in mice. [ABSTRACT FROM AUTHOR]

This report summarizes the 10th biennial meeting of The Epithelial Mesenchymal Transition International Association (TEMTIA), that took place in Paris on November 7–10, 2022. It provides a short but comprehensive introduction to the presentations and discussions that took place during the 3-day meeting. Similarly to previous TEMTIA meetings, TEMTIA X reviewed the most recent aspects of the epithelial-mesenchymal transition (EMT), a cellular process involved during distinct stages of development but also during wound healing and fibrosis to some degree. EMT has also been associated at various levels during tumor cell progression and metastasis. The meeting emphasized the intermediate stages of EMT (partial EMT or EM hybrid cells) involved in the malignant process and their potential physiological or pathological importance, taking advantage of advancements in molecular methods at the single-cell level. It also introduced novel descriptions of EMT occurrences during early embryogenesis. Sessions explored relationships between EMT and cell metabolism and how EMT can affect immune responses, particularly during tumor progression, providing new targets for cancer therapy. Finally, it introduced a new perception of EMT biological meaning based on an evolutionary perspective. The meeting integrated the TEMTIA general assembly, allowing general discussion about the future of the association and the site of the next meeting, now decided to take place in Seattle, USA, in November 2024. This report provides a comprehensive introduction to the presentations and discussions that took place during the 10th biennial meeting of TEMTIA, that occurred in Paris on November 7–10, 2022. It includes all the sessions and follows the chronological order during the 3-day meeting. A general purpose of the meeting was to explore the boundaries of the EMT process, including new concepts and developments, as illustrated by our leitmotiv for the meeting, inspired by the proximity of the Cluny Museum in Paris. [ABSTRACT FROM AUTHOR]

Promising advances in cancer therapy stemming from an increasing understanding of the molecular and genetic underpinnings of the tumorigenic process have been fueled by a strong, determined scientific community, influential patient advocacy groups and committed funding bodies. Despite these efforts, the development of effective drugs to prevent systemic dissemination of cancer cells or to eliminate overt metastasis in secondary organs remains a challenge to both researchers and physicians. In an attempt to tackle the most relevant and timely translational issues, a meeting held in 2012 as a result of a successful partnership between the Volkswagen Foundation and Nature Medicine brought together a group of metastasis research experts to identify the most important hurdles and help create a framework for potential clinical and translational strategies.

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal transition (EMT) transcription factor, confers properties of 'sternness,' such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system as a well-established paradigm of stem cell biology to evaluate Zeb1-mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1- Cre system to specifically knock out (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid-onset thymic atrophy and apoptosis-driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multilineage differentiation block were observed in Zeb1-KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multilineage differentiation genes and of cell polarity consisting of cytoskeleton-, lipid metabolism/lipid membrane-, and cell adhesion-related genes. Notably, epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1-KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients, and Zeb1 KO in the malignant counterparts of HSCs--leukemic stem cells (LSCs)--accelerated MLL-AF9- and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically coordinating HSC self-renewal, apoptotic, and multilineage differentiation fates required to suppress leukemic potential in AML., Introduction Epithelial-mesenchymal transition (EMT) is a complex process that organizes specific changes in cellular fate and phenotype and is usually accompanied by loss of cell polarity and adhesion and increased [...]

An induction in the expression of the cell adhesion receptor L1, a Wnt target gene, is a characteristic feature of Wnt/β-catenin activation in colon cancer cells at later stages of the disease. We investigated the proteins secreted following L1 expression in colon cancer cells and identified Mucin2 among the most abundant secreted proteins. We found that suppressing Mucin2 expression in L1-expressing colon cancer cells inhibits cell proliferation, motility, tumorigenesis, and liver metastasis. We detected several signaling pathways involved in Mucin2 induction in L1-expressing cells. In human colon cancer tissue, Mucin2 expression was significantly reduced or lost in the adenocarcinoma tissue, while in the mucinous subtype of colon cancer tissue, Mucin2 expression was increased. An increased signature of L1/Mucin2 expression reduced the survival rate of human colon cancer patients. Thus, induction of Mucin2 expression by L1 is required during mucinous colon cancer progression and can serve as a marker for diagnosis and a target for therapy. [ABSTRACT FROM AUTHOR]

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) regulates cellular detoxification, proliferation and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-sequencing to identify the signature of the AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGRF1 and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression was elevated in a subset of colon cancer patient samples, which also contained elevated ß-catenin levels. Remarkably, SCIN expression promoted nuclear translocation of ß-catenin and activates the WNT pathway. Our study identifies a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of ß-catenin. [ABSTRACT FROM AUTHOR]

Aberrant [beta]-catenin-TCF target gene activation plays a key role in colorectal cancer, both in the initiation stage and during invasion and metastasis. We identified the neuronal cell adhesion molecule L1, as a target gene of [beta]-catenin-TCF signaling in colorectal cancer cells. L1 expression was high in sparse cultures and coregulated with ADAM10, a metalloprotease involved in cleaving and shedding L1's extracellular domain. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis, whereas its suppression in colon cancer cells decreased motility. L1 was exclusively localized in the invasive front of human colorectal tumors together with ADAM10. The transmembrane localization and shedding of L1 by metalloproteases could be useful for detection and as target for colon cancer therapy.