Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment

Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.Magnus Zethoven, Luciano Martelotto, Andrew Pattison, Blake Bowen, Shiva Balachander, Aidan Flynn, Fernando J. Rossello, Annette Hogg, Julie A.Miller, Zdenek Frysak, Sean Grimmond, Lauren Fishbein, Arthur S. Tischler, Anthony J. Gill, Rodney J. Hicks, Patricia L. M. Dahia, Roderick Clifton-Bligh, Karel Pacak, Richard W. Tothil

Hypoglycemia as a Symptom of Neoplastic Disease, with a focus on Insulin-like Growth Factors Producing Tumors

Abstract View references (38) This article reviews the current knowledge of uncommon causes of hypoglycemia, with a focus on neoplastic disease. However, these situations are rare. They commonly accompany severely ill patients and therefore a proper diagnosis is the basis for relevant treatment. Here we discuss the pathophysiological foundation of hypoglycemia \u2013 situations caused by increased insulin production or sensitivity \u2013 but we also focus on different cytokines which could cause hypoglycemia, especially IGF-II production in what are called nonislet cell tumors. From the clinical perspective we can divide the patients who are affected into "seemingly ill\u201d or \u201chealthy patients\u201d and lead the diagnostic process accordingly. \ua9 The author(s)