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Trk Signaling Inhibition Reduces cSCC Growth and Invasion in In Vitro and Zebrafish Models and Enhances Photodynamic
Marika Quadri1, Natascia Tiso2, Marco Iuliano3
1DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Abstract:
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a rising global incidence. Neurotrophins (NTs) and their receptors, including TrkA and CD271, play key roles in epidermal homeostasis and tumor progression. We showed that CD271 expression and function are critical for low- to high-risk progression of cSCC, while TrkA is highly expressed in poorly differentiated tumors. Although NTRK fusions are recognized as oncogenic drivers, the functional impact of TrkA signaling in cSCC remains underexplored. In this study, we investigated the effects of TrkA inhibition, using both the pan-Trk inhibitor K252a and siRNA-mediated silencing, on cSCC cell lines. We evaluated cell growth and invasion in vitro, using 2D and 3D cultures, and in vivo using zebrafish xenografts. TrkA inhibition significantly reduced tumor growth and invasion, with efficacy comparable to standard chemotherapeutics (5-FU, cisplatin). Additionally, TrkA blockade downregulated mitogenic and invasive markers. Importantly, TrkA inhibition enhanced the response to photodynamic therapy in cSCC spheroids. In zebrafish, Trk-targeted interventions reduced metastatic dissemination. These findings highlight TrkA as a key regulator of cSCC survival and metastasis, suggesting its potential as a therapeutic target either alone or in combination with existing treatments.
Insights
Targeting TrkA signaling significantly inhibits cutaneous squamous cell carcinoma (cSCC) growth and metastasis. This approach shows promise as a new therapeutic strategy for skin cancer, alone or with existing treatments.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer with increasing incidence.
- Neurotrophins (NTs) and their receptors, like TrkA, are implicated in skin homeostasis and tumor progression.
- TrkA is highly expressed in poorly differentiated cSCC, but its functional role is underexplored.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting TrkA signaling in cSCC.
- To evaluate the effects of TrkA inhibition on cSCC cell growth, invasion, and metastasis.
- To assess TrkA inhibition in combination with photodynamic therapy.
Main Methods:
- Used a pan-Trk inhibitor (K252a) and siRNA to silence TrkA in cSCC cell lines.
- Assessed cell growth and invasion using 2D and 3D cultures in vitro.
- Evaluated tumor growth and metastasis in vivo using zebrafish xenografts.
Main Results:
- TrkA inhibition significantly reduced cSCC tumor growth and invasion, comparable to 5-FU and cisplatin.
- TrkA blockade downregulated key mitogenic and invasive markers.
- TrkA inhibition enhanced photodynamic therapy response in cSCC spheroids and reduced metastasis in zebrafish models.
Conclusions:
- TrkA is a critical regulator of cSCC survival and metastasis.
- Targeting TrkA represents a promising therapeutic strategy for cSCC, potentially enhancing existing treatments.
