Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

Download Full-text

Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy

Frontiers in Oncology ◽

10.3389/fonc.2021.657546 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qiu-Luo Liu ◽

Maochao Luo ◽

Canhua Huang ◽

Hai-Ning Chen ◽

Zong-Guang Zhou

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Epigenetic Regulation ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Subsequent Transformation ◽

Metastatic Cells

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial–mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal–epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.

Download Full-text

Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020)

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00977-0 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Liling Huang ◽

Shiyu Jiang ◽

Yuankai Shi

Keyword(s):

Tyrosine Kinase ◽

Solid Tumors ◽

Tyrosine Kinase Inhibitors ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Clinical Decision Making ◽

Clinical Decision ◽

Downstream Signaling ◽

The Past ◽

Treatment Paradigm

Abstract Tyrosine kinases are implicated in tumorigenesis and progression, and have emerged as major targets for drug discovery. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Over the past 20 years, multiple robust and well-tolerated TKIs with single or multiple targets including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT have been developed, contributing to the realization of precision cancer medicine based on individual patient’s genetic alteration features. TKIs have dramatically improved patients’ survival and quality of life, and shifted treatment paradigm of various solid tumors. In this article, we summarized the developing history of TKIs for treatment of solid tumors, aiming to provide up-to-date evidence for clinical decision-making and insight for future studies.

Download Full-text

Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features

Blood ◽

10.1182/blood-2011-09-380410 ◽

2012 ◽

Vol 119 (24) ◽

pp. 5782-5794 ◽

Cited By ~ 166

Author(s):

Abdel Kareem Azab ◽

Jinsong Hu ◽

Phong Quang ◽

Feda Azab ◽

Costas Pitsillides ◽

...

Keyword(s):

Multiple Myeloma ◽

Solid Tumors ◽

Peripheral Blood ◽

Therapeutic Strategy ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Hypoxic Conditions ◽

Tumor Dissemination ◽

Related Proteins

Abstract The spread of multiple myeloma (MM) involves (re)circulation into the peripheral blood and (re)entrance or homing of MM cells into new sites of the BM. Hypoxia in solid tumors was shown to promote metastasis through activation of proteins involved in the epithelial-mesenchymal transition (EMT) process. We hypothesized that MM-associated hypoxic conditions activate EMT-related proteins and promote metastasis of MM cells. In the present study, we have shown that hypoxia activates EMT-related machinery in MM cells, decreases the expression of E-cadherin, and, consequently, decreases the adhesion of MM cells to the BM and enhances egress of MM cells to the circulation. In parallel, hypoxia increased the expression of CXCR4, consequently increasing the migration and homing of circulating MM cells to new BM niches. Further studies to manipulate hypoxia to regulate tumor dissemination as a therapeutic strategy are warranted.

Download Full-text

A Reversible Shift of Driver Dependence from EGFR to Notch1 in Non-Small Cell Lung Cancer as a Cause of Resistance to Tyrosine Kinase Inhibitors

Cancers ◽

10.3390/cancers13092022 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2022

Author(s):

Francesca Iommelli ◽

Viviana De Rosa ◽

Cristina Terlizzi ◽

Rosa Fonti ◽

Rosa Camerlingo ◽

...

Keyword(s):

Kinase Inhibitors ◽

Epithelial Mesenchymal Transition ◽

Parental Cell ◽

Egfr Inhibitors ◽

Simultaneous Increase ◽

Adherent Cells ◽

Binding Assays ◽

Mesenchymal Transition ◽

Dose Dependent Decrease ◽

Dose Dependent

Notch1 plays a key role in epithelial-mesenchymal transition (EMT) and in the maintenance of cancer stem cells. In the present study we tested whether high levels of activated Notch1 in oncogene-driven NSCLC can induce a reversible shift of driver dependence from EGFR to Notch1, and thus causing resistance to EGFR inhibitors. Adherent cells (parental) and tumor spheres (TS) from NSCLC H1975 cells and patient-derived CD133-positive cells were tested for EGFR and Notch1 signaling cascade. The Notch1-dependent modulation of EGFR, NCID, Hes1, p53, and Sp1 were then analyzed in parental cells by binding assays with a Notch1 agonist, DLL4. TS were more resistant than parental cells to EGFR inhibitors. A strong upregulation of Notch1 and a concomitant downregulation of EGFR were observed in TS compared to parental cells. Parental cell exposure to DLL4 showed a dose-dependent decrease of EGFR and a simultaneous increase of NCID, Hes1, p53, and Sp1, along with the dislocation of Sp1 from the EGFR promoter. Furthermore, an enhanced interaction between p53 and Sp1 was observed in TS. In NSCLC cells, high levels of active Notch1 can promote a reversible shift of driver dependence from EGFR to Notch1, leading to resistance to EGFR inhibitors.

Download Full-text

Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

npj Precision Oncology ◽

10.1038/s41698-021-00203-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Marianne Oulhen ◽

Patrycja Pawlikowska ◽

Tala Tayoun ◽

Marianna Garonzi ◽

Genny Buson ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Copy Number ◽

Epithelial To Mesenchymal Transition ◽

Kinase Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition ◽

Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

Download Full-text

Modulation of Epithelial to Mesenchymal Transition Signaling Pathways by Olea Europaea and Its Active Compounds

International Journal of Molecular Sciences ◽

10.3390/ijms20143492 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3492 ◽

Cited By ~ 3

Author(s):

Rabiatul Adawiyah Razali ◽

Yogeswaran Lokanathan ◽

Muhammad Dain Yazid ◽

Ayu Suraya Ansari ◽

Aminuddin Bin Saim ◽

...

Keyword(s):

Olea Europaea ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Healing Process ◽

Mesenchymal Cell ◽

Cell Phenotype ◽

Wound Healing Process ◽

Active Compounds ◽

Mesenchymal Transition ◽

Olea Europaéa

Epithelial-mesenchymal transition (EMT) is a significant dynamic process that causes changes in the phenotype of epithelial cells, changing them from their original phenotype to the mesenchymal cell phenotype. This event can be observed during wound healing process, fibrosis and cancer. EMT-related diseases are usually caused by inflammation that eventually leads to tissue remodeling in the damaged tissue. Prolonged inflammation causes long-term EMT activation that can lead to tissue fibrosis or cancer. Due to activation of EMT by its signaling pathway, therapeutic approaches that modulate that pathway should be explored. Olea europaea (OE) is well-known for its anti-inflammatory effects and abundant beneficial active compounds. These properties are presumed to modulate EMT events. This article reviews recent evidence of the effects of OE and its active compounds on EMT events and EMT-related diseases. Following evidence from the literature, it was shown that OE could modulate TGFβ/SMAD, AKT, ERK, and Wnt/β-catenin pathways in EMT due to a potent active compound that is present therein.

Download Full-text

Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22095019 ◽

2021 ◽

Vol 22 (9) ◽

pp. 5019

Author(s):

Helena Oliveres ◽

David Pesántez ◽

Joan Maurel

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Tyrosine Kinases ◽

Epithelial To Mesenchymal Transition ◽

Acquired Resistance ◽

Post Translational Modification ◽

Mesenchymal Transition ◽

Igf1r Signaling ◽

Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

Download Full-text

A Role of Tumor-Released Exosomes in Paracrine Dissemination and Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms19123968 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3968 ◽

Cited By ~ 17

Author(s):

Enrico Spugnini ◽

Mariantonia Logozzi ◽

Rossella Di Raimo ◽

Davide Mizzoni ◽

Stefano Fais

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

The Body ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Target Organs

Metastatic diffusion is thought to be a multi-step phenomenon involving the release of cells from the primary tumor and their diffusion through the body. Currently, several hypotheses have been put forward in order to explain the origin of cancer metastasis, including epithelial–mesenchymal transition, mutagenesis of stem cells, and a facilitating role of macrophages, involving, for example, transformation or fusion hybridization with neoplastic cells. In this paradigm, tumor-secreted extracellular vesicles (EVs), such as exosomes, play a pivotal role in cell communications, delivering a plethora of biomolecules including proteins, lipids, and nucleic acids. For their natural role in shuttling molecules, EVs have been newly considered a part of the metastatic cascade. They have a prominent role in preparing the so-called “tumor niches” in target organs. However, recent evidence has pointed out an even more interesting role of tumor EVs, consisting in their ability to induce malignant transformation in resident mesenchymal stem cells. All in all, in this review, we discuss the multiple involvements of EVs in the metastatic cascade, and how we can exploit and manipulate EVs in order to reduce the metastatic spread of malignant tumors.

Download Full-text

Cytoplasmic NOTCH and membrane-derived β-catenin link cell fate choice to epithelial-mesenchymal transition during myogenesis

eLife ◽

10.7554/elife.14847 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 21

Author(s):

Daniel Sieiro ◽

Anne C Rios ◽

Claire E Hirst ◽

Christophe Marcelle

Keyword(s):

Cell Fate ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Epithelial Plasticity ◽

Cellular Environment ◽

Muscle Formation ◽

Fate Decision ◽

Gsk 3Β ◽

Coupling Cell

How cells in the embryo coordinate epithelial plasticity with cell fate decision in a fast changing cellular environment is largely unknown. In chick embryos, skeletal muscle formation is initiated by migrating Delta1-expressing neural crest cells that trigger NOTCH signaling and myogenesis in selected epithelial somite progenitor cells, which rapidly translocate into the nascent muscle to differentiate. Here, we uncovered at the heart of this response a signaling module encompassing NOTCH, GSK-3β, SNAI1 and β-catenin. Independent of its transcriptional function, NOTCH profoundly inhibits GSK-3β activity. As a result SNAI1 is stabilized, triggering an epithelial to mesenchymal transition. This allows the recruitment of β-catenin from the membrane, which acts as a transcriptional co-factor to activate myogenesis, independently of WNT ligand. Our results intimately associate the initiation of myogenesis to a change in cell adhesion and may reveal a general principle for coupling cell fate changes to EMT in many developmental and pathological processes.

Download Full-text

Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01161-3 ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Xuehua Chen ◽

Yongquan Huang ◽

Hui Chen ◽

Ziman Chen ◽

Jiaxin Chen ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Residual Tumor ◽

Migration And Invasion ◽

Therapeutic Effects ◽

New Paradigm ◽

Zeolitic Imidazolate Framework ◽

Mesenchymal Transition ◽

Epr Effect

Abstract Background Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied. Results Our data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial–mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo. Conclusions This work provides a new paradigm for the treatment of residual HCC after IRFA. Graphical Abstract

Download Full-text