Regulatory networks orchestrated by key transcription factors (TFs) have been proposed to play a central role in the determination of stem cell states. However, the master transcriptional regulators ...of adult stem cells are poorly understood. We have identified two TFs, Slug and Sox9, that act cooperatively to determine the mammary stem cell (MaSC) state. Inhibition of either Slug or Sox9 blocks MaSC activity in primary mammary epithelial cells. Conversely, transient coexpression of exogenous Slug and Sox9 suffices to convert differentiated luminal cells into MaSCs with long-term mammary gland-reconstituting ability. Slug and Sox9 induce MaSCs by activating distinct autoregulatory gene expression programs. We also show that coexpression of Slug and Sox9 promotes the tumorigenic and metastasis-seeding abilities of human breast cancer cells and is associated with poor patient survival, providing direct evidence that human breast cancer stem cells are controlled by key regulators similar to those operating in normal murine MaSCs.
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► Slug and Sox9 suffice to convert differentiated mammary epithelial cells to stem cells ► Maintenance of naturally arising mammary stem cells (MaSCs) requires Slug and Sox9 ► These transcription factors activate autoregulatory genetic programs to induce MaSCs ► Slug and Sox9 promote breast cancer tumor-initiating and metastatic abilities
Activation of two transcription factors, Slug and Sox9, is sufficient to convert differentiated mammary epithelial cells into stem cells and to promote metastasis in breast cancer cells.
Metastasis is the leading cause of mortality among cancer patients. Dissemination enabled by an epithelial-to-mesenchymal transition (EMT) of carcinoma cells has long been considered to be the ...predominant mechanism for carcinoma metastasis, based on overexpression studies of many EMT-inducing transcription factors. Individual CTCs – and a binary framework of EMT – have been long considered to be sufficient and necessary condition for metastasis. However, recent studies have shown that collective migration and invasion through tumor buds and clusters of Circulating Tumor Cells (CTCs) as possibly being the prevalent mode of metastasis, although individual CTCs may still contribute to metastasis. These strands and clusters have been proposed to often exhibit a hybrid epithelial/mesenchymal (E/M) phenotype where cells retain epithelial traits of cell-cell adhesion and simultaneously gain mesenchymal characteristics of migration and invasion. To highlight the crucial questions regarding metastasis, we define EMT in a non-binary and context-specific manner, suggest that it can be viewed as a trans-differentiation process, and illustrate the implications of hybrid E/M phenotype(s) and cluster-based dissemination in metastasis.
Therapeutic resistance and metastatic progression are responsible for the majority of cancer mortalities. In particular, the development of resistance is a significant barrier to the efficacy of ...cancer treatments such as chemotherapy, radiotherapy, targeted therapies, and immunotherapies. Cancer stem cells (CSCs) underlie treatment resistance and metastasis. p38 mitogen-activated protein kinase (p38 MAPK) is downstream of several CSC-specific signaling pathways, and it plays an important role in CSC development and maintenance and contributes to metastasis and chemoresistance. Therefore, the development of therapeutic approaches targeting p38 can sensitize tumors to chemotherapy and prevent metastatic progression.
The epithelial-to-mesenchymal transition (EMT) plays a critical role during normal development and in cancer progression. EMT is induced by various signaling pathways, including TGF-β, BMP, ...Wnt-β-catenin, NOTCH, Shh, and receptor tyrosine kinases. In this study, we performed single-cell RNA sequencing on MCF10A cells undergoing EMT by TGF-β1 stimulation. Our comprehensive analysis revealed that cells progress through EMT at different paces. Using pseudotime clustering reconstruction of gene-expression profiles during EMT, we found sequential and parallel activation of EMT signaling pathways. We also observed various transitional cellular states during EMT. We identified regulatory signaling nodes that drive EMT with the expression of important microRNAs and transcription factors. Using a random circuit perturbation methodology, we demonstrate that the NOTCH signaling pathway acts as a key driver of TGF-β-induced EMT. Furthermore, we demonstrate that the gene signatures of pseudotime clusters corresponding to the intermediate hybrid EMT state are associated with poor patient outcome. Overall, this study provides insight into context-specific drivers of cancer progression and highlights the complexities of the EMT process.
We report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs ...secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive CRC cells colocalized in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activation in CRC cells in a paracrine manner; these effects were blocked by immunodepletion of Jagged-1 in EC-conditioned medium or blockade of ADAM17 activity. Collectively, ECs play an active role in promoting Notch signaling and the CSC phenotype by secreting soluble Jagged-1.
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► ECs secrete soluble Jagged-1 promoting the colon cancer stem cell phenotype ► EC ADAM17 cleaves Jagged-1 to activate Notch in CRC cells via angiocrine signaling ► CD133-positive and NICD-positive CRC cells are located in the perivascular niche
A plethora of treatment options exist for cancer therapeutics, but many are limited by side effects and either intrinsic or acquired resistance. The need for more effective targeted cancer treatment ...has led to the focus on forkhead box (FOX) transcription factors as possible drug targets. Forkhead factors such as FOXA1 and FOXM1 are involved in hormone regulation, immune system modulation, and disease progression through their regulation of the epithelial-mesenchymal transition. Forkhead factors can influence cancer development, progression, metastasis, and drug resistance. In this review, we discuss the various roles of forkhead factors in biological processes that support cancer as well as their function as pioneering factors and their potential as targetable transcription factors in the fight against cancer.
Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for ...cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.
Aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with ...metastatic competence. The induction of EMT entails the loss of epithelial characteristics and the de novo acquisition of a mesenchymal phenotype. In breast cancer, the EMT state has been associated with cancer stem cell properties including expression of the stem cell-associated CD44+/CD24-/low antigenic profile, self-renewal capabilities and resistance to conventional therapies. Intriguingly, EMT features are also associated with stem cells isolated from the normal mouse mammary gland and human breast reduction tissues as well as the highly aggressive metaplastic and claudin-low breast tumor subtypes. This has implications for the origin of these breast tumors as it remains unclear whether they derive from cells that have undergone EMT or whether they represent an expansion of a pre-existing stem cell population that expresses EMT-associated markers to begin with. In the present review, we consider the current evidence connecting EMT and stem cell attributes and discuss the ramifications of these newly recognized links for our understanding of the emergence of distinct breast cancer subtypes and breast cancer progression.
The epithelial-mesenchymal transition (EMT) enables dissociation of tumour cells from the primary tumour mass, invasion through the extracellular matrix, intravasation into blood vessels and ...colonisation of distant organs. Cells that revert to the epithelial state via the mesenchymal-epithelial transition cause metastases, the primary cause of death in cancer patients. EMT also empowers cancer cells with stem-cell properties and induces resistance to chemotherapeutic drugs. Understanding the driving factors of EMT is critical for the development of effective therapeutic interventions.
This manuscript describes the generation of a database containing EMT gene signatures derived from cell lines, patient-derived xenografts and patient studies across cancer types and multiomics data and the creation of a web-based portal to provide a comprehensive analysis resource.
EMTome incorporates (i) EMT gene signatures; (ii) EMT-related genes with multiomics features across different cancer types; (iii) interactomes of EMT-related genes (miRNAs, transcription factors, and proteins); (iv) immune profiles identified from The Cancer Genome Atlas (TCGA) cohorts by exploring transcriptomics, epigenomics, and proteomics, and drug sensitivity and (iv) clinical outcomes of cancer cohorts linked to EMT gene signatures.
The web-based EMTome portal is a resource for primary and metastatic tumour research publicly available at www.emtome.org .
Mechanisms of cancer metastasis Castaneda, Maria; den Hollander, Petra; Kuburich, Nick A. ...
Seminars in cancer biology,
December 2022, 2022-12-00, 20221201, Letnik:
87
Journal Article
Recenzirano
Odprti dostop
Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires ...understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient’s mutation and/or immune profile are also highlighted.
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