Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer

Seeneevassen, Lornella; Giraud, Julie; Molina-Castro, Silvia; Sifré, Elodie; Tiffon, Camille; Beauvoit, Clémentine; Staedel, Cathy; Mégraud, Françis; Lehours, Philippe; Martin, Océane; Bœuf, Hélène; Dubus, Pierre; Varon, Christine

doi:10.3390/cancers12082011

Cited by 33 publications

(47 citation statements)

References 46 publications

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“…Additionally, in the TNBC cell line MDA-MB-231, LIFR overexpression did not alter vimentin protein levels in vitro but reduced vimentin positive metastatic foci in vivo [ 102 ]. The anti-tumorigenic roles of LIF in gastric CSCs also have been described, where it decreased the CSC properties and population in both cell lines and a patient-derived xenograft (PDX) [ 105 ] ( Figure 2 ). Both in breast and in gastric cancer cells, the anti-metastatic role of LIF-LIFR was mediated through the activation of Hippo tumour suppressor kinases (MST1/2 and LATS1/2), with the consequent inhibition of the YAP/TAZ/TEAD oncogenic effector activity.…”

Section: Role Of Lif On Epithelial-mesenchymal Plasticitymentioning

confidence: 96%

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

Abaurrea

Araujo

Caffarel

2021

IJMS

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Epithelial–mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.

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Section: Role Of Lif On Epithelial-mesenchymal Plasticitymentioning

confidence: 96%

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

Abaurrea

Araujo

Caffarel

2021

IJMS

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“…XMU-MP-1 is the chemical probe widely being used to study the Hippo pathway. Several publications have described the cellular roles of MST1/2 in the Hippo pathway with XMU-MP-1, assuming the molecule can pharmacologically inhibit the function of MST1/2 [54,[57][58][59][60][61][62][63].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

2022

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A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine learning (ML) classifiers, and validated by biochemical and biophysical experiments. ML trained by CA I and CA II inhibitor molecular fingerprints predicted candidates from the protein-specific bioactive molecules approved or under clinical trials. For experimental tests, three sulfonamide-containing kinase inhibitors, 5932, 5946, and 6046, were chosen. The enzyme assays with CA I, CA II, CA IX, and CA XII have allowed the quantitative comparison in the molecules’ inhibitory activities. While 6046 inhibited weakly, 5932 and 5946 exhibited potent inhibitions with 100 nM to 1 mM inhibitory constants. The ML screening was extended for finding CAs inhibitors of all known kinase inhibitors. It found XMU-MP-1 as another potent CA inhibitor with an approximate 30 nM inhibitory constant for CA I, CA II, and CA IX. Differential scanning fluorimetry confirmed the direct interaction between CAs and small molecules. Cheminformatics studies, including docking simulation, suggest that each molecule possesses two separate functional moieties: one for interaction with kinases and the other with CAs.

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“…LIF is a key regulator of CSCs [ 10 ], plays a role in stem-cell maintenance [ 12 , 13 , 36 ], regulates self-renewal and pluripotency [ 12 ], and is associated with chemoresistance [ 14 , 15 ]. Subsequently, LIF/LIFR activates multiple signaling pathways including JAK/STAT3 as immediate effectors, and concurrent MAPK, AKT, and mTOR activation further downstream, all of which are implicated in EC progression [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer

et al. 2021

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Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.

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Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer

Cited by 33 publications

References 46 publications

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer

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