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Functional mapping of receptor tyrosine kinases in myxoid liposarcoma
Tiziana Negri1, Emanuela Virdis, Silvia Brich
1Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Purpose:
The aim of this study was to analyze receptor tyrosine kinases (RTK) and their downstream signaling activation profile in myxoid liposarcomas (MLS) by investigating 14 molecularly profiled tumors: 7 naive and 7 treated with conventional chemotherapy/radiotherapy or the new drug trabectedin.
Experimental Design:
Frozen and matched formalin-fixed, paraffin-embedded material from surgical specimens were analyzed using biochemical, molecular, and molecular/cytogenetic approaches, complemented by immunohistochemistry and confocal microscopy.
Results:
In the absence of any RTK and downstream effector deregulation, the naive cases revealed epidermal growth factor receptor, platelet-derived growth factor receptor B, RET, and MET activation sustained by autocrine/paracrine loops, and RTK cross-talk as a result of heterodimerization. Interestingly, RET and MET activation seems to play a major role in the pathogenesis of MLS by involving different targets through different mechanisms. RET activation (which may activate MET) involves the tumoral vascular component by means of RET/MET cross-talk and VEGFA (vascular endothelial growth factor A)/GFRalpha3 (glial cell-derived neurotrophic factor family receptor alpha3)/artemin-mediated signaling as revealed by VEGF receptor 2/RET coimmunoprecipitation. MET activation involves the cellular tumor component by means of a direct ligand-dependent loop and indirect GFRalpha3 (RET coreceptor)/artemin-mediated signaling. About downstream signaling, the association of AKT activation with the round cell variant is interesting. No relevant changes in the original RTK activation profiles were observed in the posttreatment cases, a finding that is in keeping with the nontargeted treatments used.
Conclusions:
These findings highlight the particular cell-specific activation profile of RET/GFRalpha3 and MET in MLS, and the close correlation between AKT activation and the round cell variant, thus opening up new therapeutic perspectives for MET/AKT inhibitors and antagonistic small molecules binding GFRalpha3.
Insights
Receptor tyrosine kinases (RTK) like RET and MET are activated in myxoid liposarcomas (MLS), driving tumor growth. AKT activation correlates with the round cell variant, suggesting new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Myxoid liposarcomas (MLS) are soft tissue tumors with complex molecular signaling.
- Understanding receptor tyrosine kinase (RTK) activation is crucial for developing targeted therapies.
Purpose of the Study:
- To analyze RTK activation profiles in naive and treated myxoid liposarcomas.
- To investigate downstream signaling pathways involved in MLS pathogenesis.
Main Methods:
- Analysis of 14 molecularly profiled MLS tumors (7 naive, 7 treated).
- Utilized biochemical, molecular, cytogenetic, immunohistochemistry, and confocal microscopy techniques.
- Examined frozen and formalin-fixed, paraffin-embedded tissue samples.
Main Results:
- Naive MLS showed activation of epidermal growth factor receptor, platelet-derived growth factor receptor B, RET, and MET, sustained by autocrine/paracrine loops and RTK cross-talk.
- RET and MET activation play key roles in MLS pathogenesis, involving distinct cellular components and signaling pathways.
- RET activation impacts tumor vasculature via RET/MET cross-talk and VEGFA/GFRalpha3/artemin signaling.
- MET activation affects the cellular tumor component through ligand-dependent loops and GFRalpha3/artemin signaling.
- AKT activation was associated with the round cell variant of MLS.
- No significant changes in RTK activation were observed in post-treatment cases.
Conclusions:
- RET/GFRalpha3 and MET exhibit cell-specific activation profiles in MLS.
- A strong correlation exists between AKT activation and the round cell variant.
- These findings suggest potential therapeutic strategies targeting MET/AKT pathways and GFRalpha3.
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