Epithelial-Mesenchymal Transition Induces Endoplasmic-Reticulum-Stress Response in Human Colorectal Tumor Cells

Tumor cells are stressed by unfavorable environmental conditions like hypoxia or starvation. Driven by the resulting cellular stress tumor cells undergo epithelial-mesenchymal transition. Additionally, cellular stress is accompanied by endoplasmic reticulum-stress which induces an unfolded protein response. It is unknown if epithelial-mesenchymal transition and endoplasmic reticulum-stress are occurring as independent parallel events or if an interrelationship exists between both of them. Here, we show that in colorectal cancer cells endoplasmic reticulum-stress depends on the induction of ZEB-1, which is a main factor of epithelial-mesenchymal transition. In the absence of ZEB-1 colorectal cancer cells cannot mount endoplasmic reticulum-stress as a reaction on cellular stress situations like hypoxia or starvation. Thus, our data suggest that there is a hierarchy in the development of cellular stress which starts with the presence of environmental stress that induces epithelial-mesenchymal transition which allows finally endoplasmic reticulum-stress. This finding highlights the central role of epithelial-mesenchymal transition during the process of tumorigenesis as epithelial-mesenchymal transition is also associated with chemoresistance and cancer stemness. Consequently, endoplasmic reticulum-stress might be a well suited target for chemotherapy of colorectal cancers

Upholding a role for EMT in pancreatic cancer metastasis

Epithelial-to-mesenchymal transition (EMT) is a cellular program that operates in the context of embryogenesis, wound healing and carcinoma pathogenesis to drive epithelial cells towards a mesenchymal state. During carcinoma progression, EMT enables the cells forming these tumours to acquire the traits of highly malignant cells, notably motility, invasiveness and an ability to disseminate to form distant metastases. Indeed, a number of published reports have associated EMT with a variety of malignant carcinoma cells. Recently, however, Zheng et al.1 reported that in genetically engineered mouse models of pancreatic adenocarcinoma development, carcinoma cells could metastasize without activating EMT programs. Their conclusions, if sustained by the evidence presented, would prompt a major change in how we conceptualize malignant progression and metastasis of carcinoma cells, including the neoplastic cells in human carcinomas

Zeb1 maintains long-term adult hematopoietic stem cell function and extramedullary hematopoiesis

Emerging evidence implicates the epithelial-mesenchymal transition (EMT) transcription factor Zeb1 as a critical regulator of hematopoietic stem cell (HSC) differentiation. Whether Zeb1 regulates long-term maintenance of HSC function remains an open question. Through use of an inducible Mx-1 Cre mouse model that deletes conditional Zeb1 alleles in the adult hematopoietic system, we found that mice engineered to be deficient in Zeb1 for 32 weeks displayed expanded immunophenotypically defined adult HSCs and multi-potent progenitors associated with increased abundance of lineage-biased/balanced HSC subsets and augmented cell survival characteristics. During hematopoietic differentiation, persistent Zeb1 loss increased B-cells in the bone marrow and spleen and decreased monocyte generation in the peripheral blood. Using competitive transplantation experiments, we found that HSCs from adult mice with long-term Zeb1 deletion displayed a cell autonomous defect in multi-lineage differentiation capacity. Long-term Zeb1 loss perturbed extramedullary hematopoiesis characterized by increased splenic weight and a paradoxical reduction in splenic cellularity that was accompanied by HSC exhaustion, lineage specific defects and an accumulation of aberrant, pre-leukemic like c-kit+CD16/32+ progenitors. Loss of Zeb1 for up to 42 weeks can lead to progressive splenomegaly and an accumulation of Gr-1+Mac-1+ cells, further supporting the notion that long-term expression of Zeb1 suppresses pre-leukemic activity. Thus, sustained Zeb1 deletion disrupts HSC functionality in vivo and impairs regulation of extramedullary hematopoiesis with potential implications for tumor suppressor functions of Zeb1 in myeloid neoplasms

A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells

The embryonic programme ‘epithelial–mesenchymal transition' (EMT) is thought to promote malignant tumour progression. The transcriptional repressor zinc-finger E-box binding homeobox 1 (ZEB1) is a crucial inducer of EMT in various human tumours, and was recently shown to promote invasion and metastasis of tumour cells. Here, we report that ZEB1 directly suppresses transcription of microRNA-200 family members miR-141 and miR-200c, which strongly activate epithelial differentiation in pancreatic, colorectal and breast cancer cells. Notably, the EMT activators transforming growth factor β2 and ZEB1 are the predominant targets downregulated by these microRNAs. These results indicate that ZEB1 triggers an microRNA-mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells. Alternatively, depending on the environmental trigger, this loop might switch and induce epithelial differentiation, and thus explain the strong intratumorous heterogeneity observed in many human cancers

The EMT transcription factor ZEB1 blocks osteoblastic differentiation in bone development and osteosarcoma

Osteosarcoma is an often-fatal mesenchyme-derived malignancy in children and young adults. Overexpression of EMT-transcription factors (EMT-TFs) has been associated with poor clinical outcome. Here, we demonstrated that the EMT-TF ZEB1 is able to block osteoblastic differentiation in normal bone development as well as in osteosarcoma cells. Consequently, overexpression of ZEB1 in osteosarcoma characterizes poorly differentiated, highly metastatic subgroups and its depletion induces differentiation of osteosarcoma cells. Overexpression of ZEB1 in osteosarcoma is frequently associated with silencing of the imprinted DLK-DIO3 locus, which encodes for microRNAs targeting ZEB1. Epigenetic reactivation of this locus in osteosarcoma cells reduces ZEB1 expression, induces differentiation, and sensitizes to standard treatment, thus indicating therapeutic options for ZEB1-driven osteosarcomas. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

The Advocate

Headlines Include: Laurels For Feerick: An Alumnus To Remember; Crime at Fordham; Who\u27s Next?, Film at 11https://ir.lawnet.fordham.edu/student_the_advocate/1007/thumbnail.jp

The transcription factor ZEB1 regulates stem cell self-renewal and cell fate in the adult hippocampus

Radial glia-like (RGL) stem cells persist in the adult mammalian hippocampus, where they generate new neurons and astrocytes throughout life. The process of adult neurogenesis is well documented, but cellautonomous factors regulating neuronal and astroglial differentiation are incompletely understood. Here, we evaluate the functions of the transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) in adult hippocampal RGL cells using a conditional-inducible mouse model. We find that ZEB1 is necessary for self-renewal of active RGL cells. Genetic deletion of Zeb1 causes a shift toward symmetric cell division that consumes the RGL cell and generates pro-neuronal progenies, resulting in an increase of newborn neurons and a decrease of newly generated astrocytes. We identify ZEB1 as positive regulator of the ets-domain transcription factor ETV5 that is critical for asymmetric divisio

Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, confers properties of ‘stemness’, 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 knockout (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 multi-lineage differentiation block was observed in Zeb1 KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multi-lineage 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 co-ordinating HSC self-renewal, apoptotic and multi-lineage differentiation fates required to suppress leukemic potential in AML