Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Activation of RAS Signalling is Associated with Altered Cell Adhesion in Phaeochromocytoma

Phaeochromocytomas and paragangliomas (PPGLs) are neuroendocrine catecholamine-producing tumours that may progress into inoperable metastatic disease. Treatment options for metastatic disease are limited, indicating a need for functional studies to identify pharmacologically targetable pathophysiological mechanisms, which require biologically relevant experimental models. Recently, a human progenitor phaeochromocytoma cell line named "hPheo1" was established, but its genotype has not been characterised. Performing exome sequencing analysis, we identified a KIF1B T827I mutation, and the oncogenic NRAS Q61K mutation. While KIF1B mutations are recurring somatic events in PPGLs, NRAS mutations have hitherto not been detected in PPGLs. Therefore, we aimed to assess its implications for the hPheo1 cell line, and possible relevance for the pathophysiology of PPGLs. We found that transient downregulation of NRAS in hPheo1 led to elevated expression of genes associated with cell adhesion, and enhanced adhesion to hPheo1 cells extracellular matrix. Analyses of previously published mRNA data from two independent PPGL patient cohorts (212 tissue samples) revealed a subcluster of PPGLs featuring hyperactivated RAS pathway-signalling and under-expression of cell adhesion-related gene expression programs. Thus, we conclude that NRAS activity in hPheo1 decreases adhesion to their own extracellular matrix and mirrors a transcriptomic RAS-signalling-related phenomenon in PPGLs.Funding Agencies|ALF Grants, Region Ostergotland [LIO-532021]; Medical Research Council of Southeast Sweden [FORSS-481781]; LiU Cancer, Linkoping University</p

The Yin and Yang Between Plasma Glucose Levels and Cortisol Replacement Therapy in Schmidt’s Syndrome

Objective: To illustrate how steroid replacement in adrenal insufficiency can influence the development of hypoglycemia in a patient with type 1 diabetes mellitus (T1D). Methods: We describe the case of a 36-year-old female patient with T1D and Addison’s disease (Schmidt’s syndrome) on multiple daily insulin injections who presented with recurrent hypoglycemia despite being on physiological replacement doses of hydrocortisone. Results: With the assistance of continuous glucose monitoring technology, a pattern of nocturnal hypoglycemia was clearly identified. The patient was taking her hydrocortisone 15 mg in the morning and 5 mg in the early afternoon. With the short half-life of oral hydrocortisone, the evening decline in plasma cortisol concentration led to an increased susceptibility to recurrent evening and nocturnal hypoglycemia. Hypoglycemic episodes were resolved when her morning hydrocortisone dose was changed and prednisolone was added to a later time in the evening. Conclusion: Patients with Schmidt’s syndrome can be susceptible to nocturnal hypoglycemia with inadequate steroid replacement. Identifying patients at risk for hypoglycemia in Schmidt’s syndrome provides an opportunity for precision management beyond the manipulation of antihyperglycemic agents

Case report : Two sisters with a germline CHEK2 variant and distinct endocrine neoplasias

Genetic testing has become the standard of care for many disease states. As a result, physicians treating patients who have tumors often rely on germline genetic testing results for making clinical decisions. Cases of two sisters carrying a germline CHEK2 variant are highlighted whereby possible other genetic drivers were discovered on tumor analysis. CHEK2 (also referred to as CHK2) loss of function has been firmly associated with breast cancer development. In this case report, two siblings with a germline CHEK2 mutation also had distinct endocrine tumors. Pituitary adenoma and pancreatic neuroendocrine tumor (PNET) was found in the first sibling and pheochromocytoma (PCC) discovered in the second sibling. Although pituitary adenomas, PNETs, and PCC have been associated with NF1 gene mutations, the second sister with a PCC did have proven germline CHEK2 with a pathogenic somatic NF1 mutation. We highlight the clinical point that unless the tumor is sequenced, the real driver mutation that is causing the patients tumor may remain unknown.Funding Agencies|NIGMS [GM114102]; CTSA-IIMS (NIH/NCATS Grant) [UL1TR001120, UL1 TR002645]; Mays Cancer Center NIH-NCI [P30 CA54174]; Alexs Lemonade Stand Foundation; Northwest Mutual/Flashes of Hope; Gatorade Trust</p