Osteosarcoma (OS) is an aggressive mesenchymal tumor for which no molecularly targeted therapies are available. We have previously identified TRAF2- and NCK-interacting protein kinase (TNIK) as an essential factor for the transactivation of Wnt signal target genes and shown that its inhibition leads to eradication of colorectal cancer stem cells. The involvement of Wnt signaling in the pathogenesis of OS has been implicated. The aim of the present study was to examine the potential of TNIK as a therapeutic target in OS. RNA interference or pharmacological inhibition of TNIK suppressed the proliferation of OS cells. Transcriptome analysis suggested that a small-molecule inhibitor of TNIK upregulated the expression of genes involved in OS cell metabolism and downregulated transcription factors essential for maintaining the stem cell phenotype. Metabolome analysis revealed that this TNIK inhibitor redirected the metabolic network from carbon flux toward lipid accumulation in OS cells. Using in vitro and in vivo OS models, we confirmed that TNIK inhibition abrogated the OS stem cell phenotype, simultaneously driving conversion of OS cells to adipocyte-like cells through induction of PPARγ. In relation to potential therapeutic targeting in clinical practice, TNIK was confirmed to be in an active state in OS cell lines and clinical specimens. From these findings, we conclude that TNIK is applicable as a potential target for treatment of OS, affecting cell fate determination.

Background Takotsubo syndrome (TTS) is an acute and usually reversible heart failure syndrome characterised as an uncommon left ventricular (LV) cardiomyopathy. Recurrence of TTS is rare, estimated to be 1-6%. We report a rare case of TTS that occurred three times in two months but manifested various phenotypes. Case summary A 68-year-old woman was admitted to our hospital with acute-onset chest pain and hypertension. The coronary angiography findings were normal, although left ventriculography (LVG) revealed inferior wall hypokinesis, leading to a mid-ventricular TTS diagnosis. She was discharged on day 3 after her symptoms improved and vitals stabilised. The patient’s condition remained uneventful until two weeks post discharge, when acute chest pain and hypertension recurred. She was admitted again with the same diagnosis. However, LV morphology revealed an apical ballooning pattern, with inferior LV wall hypokinesis. She was discharged on day 7 after her symptoms and electrocardiography findings improved but was readmitted again two weeks later after acute chest pain and hypertension recurred. LVG performed a third time demonstrated mid-ventricular TTS. The patient was prescribed additional medications and discharged on day 12. Her electrocardiography findings normalised, and the patient remained asymptomatic without recurrence four months after the initial presentation. Discussion Recurrence and phenotypic change of TTS is rare. Some cases have been reported but occurring months to years after initial diagnosis. Combined treatment with β-blockers and angiotensin converting enzyme inhibitors or angiotensin receptor antagonists may be more effective to prevent the recurrence than monotherapies.