The PLEKHA1-TACC2 fusion gene drives tumorigenesis via vascular mimicry formation in esophageal squamous-cell carcinoma

Abstract Despite advancements of diagnosis and multimodality therapies in esophageal squamous-cell carcinoma (ESCC), the survival is still unsatisfactory. Therefore, it is urgent to identify novel targets for efficient therapeutic strategies. Herein, we identify a fusion gene between PLEKHA1 and TACC2 generated by chromosomal rearrangement by performing RNA sequencing from ESCC tissues. PLEKHA1-TACC2 transcripts are present in ESCC (66/404, 16.3%) and head and neck squamous cell carcinoma (58/402, 14.4%) tissues, correlated with poor prognosis of patients. Mechanistically, the fusion proteins upregulate the EphA2/AKT/MMP2 signaling pathway and promote vascular mimicry formation by reducing the ubiquitylation of EphA2. Moreover, EphA2 inhibitors dasatinib and ALW II-41-27 remarkably suppress the progression of tumors expressing PLEKHA1-TACC2 in vivo. Functionally, PLEKHA1-TACC2 fusion and Trp53 deletion significantly increases tumor incidence, tumor multiplicity, and mouse mortality in transgenic ESCC mouse model, which could be suppressed by regorafenib, a EphA2 inhibitor approved by FDA in solid tumors. Together, our data indicate that PLEKHA1-TACC2 fusion protein has oncogenic activities and serves as a promising prognosis marker and therapeutic target.