Wnt/ß-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours.

We show that activation of Wnt/ß-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of ß-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that ß-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking ß-catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against ß-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri-methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell-associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/ß-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which ß-catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours.

Challenges in Histologic Diagnosis of Nonchordomatous Lesions of the Clivus.

IMPORTANCE: Nonchordomatous clival lesions are rare and represent a wide range of different benign and malignant pathologies. For an accurate and specific final diagnosis, biopsy procedures and/or resections followed by histologic examination are mandatory. OBJECTIVE: To illustrate the challenges in obtaining a final histologic diagnosis in patients with various types of clival lesions. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of medical records of 24 patients who underwent endonasal endoscopic biopsy of the clivus between February 1, 2005, and June 1, 2013, in 2 medical university hospitals. Analysis was conducted between January 1 and August 15, 2014. INTERVENTIONS: All patients underwent endoscopic biopsy of the clivus. MAIN OUTCOMES AND MEASURES: The number of biopsies performed to establish a diagnosis in clival lesions and the problems encountered when analyzing the radiologic findings and histologic results. RESULTS: In 14 of 24 patients (58%), a conclusive histologic diagnosis of the nonchordomatous clival lesion could be determined. Despite up to 3 endonasal endoscopic biopsies, the histologic result could not be clearly specified in the remaining 10 patients (42%). No major complications occurred. Treatment based on the testing results included endonasal endoscopic surgery, radiotherapy or radiochemotherapy, and/or follow-up examination. CONCLUSIONS AND RELEVANCE: Challenges can occur in the radiologic evaluation and pathologic differentiation of diverse bone lesions with overlapping morphologic features as well as in the differentiation between neoplastic, reactive, inflammatory, and metabolic bone lesions and developmental disorders. Despite more than 1 biopsy, histologic classification will not always lead to a definitive diagnosis. In such cases, an interdisciplinary team should decide whether additional biopsies should be performed or whether clinical, endoscopic, and radiologic controls are sufficient.