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Translational Therapeutics

Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications

Abstract

Background

Occurrence of squamous cell carcinoma (SCC) even in early-stage, untreated chronic lymphocytic leukemia (CLL) patients can be a significant morbidity issue with occasional transformation into metastatic skin lesions.

Methods

CLL cells and extracellular vesicles (EVs) from CLL patients’ blood/plasma were purified and used. Expression/activation of AXL and its functions in normal keratinocytes (HEKa) were assessed in vitro co-culture system and in SCC tissues.

Results

We detected aberrant activation of AXL, AKT and ERK-1/2 in SCC cell lines compared to HEKa. We also detected increased expression of AXL in primary SCC tissues obtained from CLL patients. Increased activation of AXL, AKT, ERK-1/2 and Src was discernible in HEKa upon co-culturing with CLL cells. Further analysis suggests that Gas6, a ligand of AXL, regulates AXL activation in co-cultured HEKa. Interestingly, exposure of HEKa cells to CLL plasma-derived EVs induced expression of AXL, P-AKT, and EMT-associated markers leading to migration of the cells. Finally, pharmacologic inhibition of AXL induced cell death in SCC lines in a dose dependent manner.

Conclusions

Our findings that CLL cells likely are involved in driving SCC progression, at least in part, via activation of the AXL signaling axis, indicating that AXL inhibition may be beneficial for our CLL patients with SCC.

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Fig. 1: AXL RTK expression and activation status in SCC cell lines and in tissue biopsies.
Fig. 2: AXL kinase Inhibitor TP-0903 induces apoptosis in SCC cells.
Fig. 3: CLL cells activate AXL signaling in HEKa cells.
Fig. 4: Gas6 activates HEKa cells and impacts of AXL kinase Inhibitor TP-0903 on HEKa cell activation.
Fig. 5: EVs from CLL plasma activates HEKa cells.
Fig. 6: Interaction between CLL cells with normal keratinocytes.

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Data availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.

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Acknowledgements

We would like to thank our CLL patients who participated in this study. We would also like to thank Dr. Akhilesh Pandey, Dr. Svetomir N. Markovic and Dr. Aleksandar Sekulic for their generous help with providing reagents needed for the study. We are thankful to Tammy Hughes for all her administrative support. Henry J. Predolin Foundation has generously supported the Mayo Clinic Hematology Biobanking efforts for collecting blood samples that were used for the research published.

Funding

This work was supported by Mayo Internal Funding.

Author information

Authors and Affiliations

Authors

Contributions

Study conception and design: S.S and N.E.K; Acquisition, analysis, or interpretation of data: S.S, R.G, M.D.B, W.H, J.B, and L.E.W; Drafting of the manuscript: S.S, R.G, A.K.G and N.E.K; Technical, or material support: S.S, R.G and N.E.K; All authors contributed to revising the manuscript, and all authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Sutapa Sinha or Neil E. Kay.

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Competing interests

SS, RG, MDB, WH, JB, LEW, AKG-No conflicts. NEK-Advisory Board for: AbbVie, Astra Zeneca, Beigene, Behring, Boehringer Ingelheim Pharmaceuticals, Inc., Dava Oncology, Janssen, Juno Therapeutics, Pharmacyclics. DSMC (Data Safety Monitoring Committee) for: Agios Pharm, Astra Zeneca, BMS –Celgene, Dren Bio Janssen, Research funding from: AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, Pharmacyclics, Sunesis, Vincerx.

Ethics approval and consent to participate

All healthy individuals and CLL patients provided written informed consent according to the Declaration of Helsinki to the Mayo Clinic Institutional Review Board, which approved these studies.

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Sinha, S., Guo, R., Del Busso, M.D. et al. Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02752-1

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