ORCID Profile
0000-0003-2226-3517
Current Organisation
Uppsala University
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Publisher: Cold Spring Harbor Laboratory
Date: 15-10-2017
Abstract: Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas G12D in mouse lung epithelial cells markedly impairs the progression of KRas G12D -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas G12D -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
Publisher: Springer Science and Business Media LLC
Date: 13-07-2015
DOI: 10.1038/NATURE14664
Publisher: Bioscientifica
Date: 10-2015
DOI: 10.1530/ERC-15-0321
Abstract: Aldosterone-producing adenomas (APAs) are found in 1.5–3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D , ATP1A1 and ATP2B3 , also important for membrane potential/intracellular Ca 2 + regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D , ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1 / ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT , in ATP1A1 / ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca 2 + levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.
Publisher: The Endocrine Society
Date: 11-2009
DOI: 10.1210/JC.2009-0546
Abstract: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. The Weiss score is the most widely accepted method for distinguishing an ACC from an adrenocortical adenoma (ACA) however, in borderline cases, accurate diagnosis remains problematic. We recently discovered that the glucocorticoid receptor (GR) gene NR3C1 is significantly up-regulated in ACCs compared with ACAs in global gene expression studies. Our objective was to study GR expression in adrenocortical tumors (ACTs) and to assess its utility as an adjunct to the Weiss score. Microarray analysis, real-time quantitative RT-PCR (qPCR), immunohistochemistry, Western blot, and direct sequencing were performed. Analysis of 28 ACTs by microarray and 49 ACTs by qPCR found NR3C1 expression to be up-regulated in ACCs compared with ACAs (P < 0.001). Western blotting and RT-PCR confirmed the presence of the GRalpha isoform in ACCs, and no mutations were detected on direct sequencing. Immunohistochemistry for GR in an overlapping cohort of ACTs demonstrated strongly positive nuclear staining in 31 of 33 ACCs (94%), with negative staining in 40 of 41 ACAs (98%) (P < 0.001). This finding was validated in an external cohort of ACTs, such that 14 of 18 ACCs (78%) demonstrated positive nuclear staining whereas 32 of 33 ACAs (94%) were negative (P < 0.001). The immunohistochemical finding of nuclear GR staining identified ACCs with high diagnostic accuracy. We propose that GR immunohistochemistry may complement the Weiss score in the diagnosis of ACC in cases that display borderline histology. The possibility that GR is transcriptionally active in these tumors, and may therefore be a therapeutic target, requires further study.
Publisher: Public Library of Science (PLoS)
Date: 27-07-2012
Publisher: Archives of Pathology and Laboratory Medicine
Date: 05-2018
DOI: 10.5858/ARPA.2017-0245-RA
Abstract: The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, in conjunction with the International Mesothelioma Interest Group, the International Thymic Malignancy Interest Group, and the Worldwide Esophageal Cancer Collaboration, developed proposals for the 8th edition of their respective tumor, node, metastasis (TNM) staging classification systems. To review these changes and discuss issues for the reporting pathologist. Proposals were based on international databases of lung (N = 94 708), with an external validation using the US National Cancer Database mesothelioma (N = 3519) thymic epithelial tumors (10 808) and epithelial cancers of the esophagus and esophagogastric junction (N = 22 654). These proposals have been mostly accepted by the Union for International Cancer Control and the American Joint Committee on Cancer and incorporated into their respective staging manuals (2017). The Union for International Cancer Control recommended implementation beginning in January 2017 however, the American Joint Committee on Cancer has deferred deployment of the eighth TNM until January 1, 2018, to ensure appropriate infrastructure for data collection. This manuscript summarizes the updated staging of thoracic malignancies, specifically highlighting changes from the 7th edition that are relevant to pathologic staging. Histopathologists should become familiar with, and start to incorporate, the 8th edition staging in their daily reporting of thoracic cancers henceforth.
No related grants have been discovered for Johan Botling.