Gioia Iezza
University of California, San Francisco
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Publication
Featured researches published by Gioia Iezza.
Cancer Research | 2011
Roch-Philippe Charles; Gioia Iezza; Elena Amendola; David Dankort; Martin McMahon
Mutated BRAF is detected in approximately 45% of papillary thyroid carcinomas (PTC). To model PTC, we bred mice with adult-onset, thyrocyte-specific expression of BRAF(V600E). One month following BRAF(V600E) expression, mice displayed increased thyroid size, widespread alterations in thyroid architecture, and dramatic hypothyroidism. Over 1 year, without any deliberate manipulation of tumor suppressor genes, all mice developed PTC displaying nuclear atypia and marker expression characteristic of the human disease. Pharmacologic inhibition of MEK1/2 led to decreased thyroid size, restoration of thyroid form and function, and inhibition of tumorigenesis. Mice with BRAF(V600E)-induced PTC will provide an excellent system to study thyroid tumor initiation and progression and the evaluation of inhibitors of oncogenic BRAF signaling.
Molecular Cancer Research | 2014
Roch-Philippe Charles; Jillian M. Silva; Gioia Iezza; Wayne A. Phillips; Martin McMahon
Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer-related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3′-Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAFV600E, we previously developed a model of PTC. However, as in humans, BRAFV600E-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CAH1047R is unable to drive transformation on its own, when combined with BRAFV600E in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAFV600E cooperates with either PIK3CAH1074R or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma. Implications: This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma. Mol Cancer Res; 12(7); 979–86. ©2014 AACR.
Genes & Development | 2014
Joseph Juan; Teruyuki Muraguchi; Gioia Iezza; Rosalie C. Sears; Martin McMahon
Oncogene-induced senescence (OIS) is proposed as a cellular defense mechanism that restrains malignant progression of oncogene-expressing, initiated tumor cells. Consistent with this, expression of BRAF(V600E) in the mouse lung epithelium elicits benign tumors that fail to progress to cancer due to an apparent senescence-like proliferative arrest. Here we demonstrate that nuclear β-catenin → c-MYC signaling is essential for early stage proliferation of BRAF(V600E)-induced lung tumors and is inactivated in the subsequent senescence-like state. Furthermore, either β-catenin silencing or pharmacological blockade of Porcupine, an acyl-transferase essential for WNT ligand secretion and activity, significantly inhibited BRAF(V600E)-initiated lung tumorigenesis. Conversely, sustained activity of β-catenin or c-MYC significantly enhanced BRAF(V600E)-induced lung tumorigenesis and rescued the anti-tumor effects of Porcupine blockade. These data indicate that early stage BRAF(V600E)-induced lung tumors are WNT-dependent and suggest that inactivation of WNT → β-catenin → c-MYC signaling is a trigger for the senescence-like proliferative arrest that constrains the expansion and malignant progression of BRAF(V600E)-initiated lung tumors. Moreover, these data further suggest that the trigger for OIS in initiated BRAF(V600E)-expressing lung tumor cells is not simply a surfeit of signals from oncogenic BRAF but an insufficiency of WNT → β-catenin → c-MYC signaling. These data have implications for understanding how genetic abnormalities cooperate to initiate and promote lung carcinogenesis.
Cancer Research | 2013
Christy L. Trejo; Shon Green; Victoria Marsh; Eric A. Collisson; Gioia Iezza; Wayne A. Phillips; Martin McMahon
Adenocarcinoma of the lung, a leading cause of cancer death, frequently displays mutational activation of the KRAS proto-oncogene but, unlike lung cancers expressing mutated EGFR, ROS1, or ALK, there is no pathway-targeted therapy for patients with KRAS-mutated lung cancer. In preclinical models, expression of oncogenic KRAS(G12D) in the lung epithelium of adult mice initiates development of lung adenocarcinoma through activation of downstream signaling pathways. In contrast, mutationally activated BRAF(V600E), a KRAS effector, fails to initiate lung carcinogenesis despite highly efficient induction of benign lung tumorigenesis. To test if phosphoinositide 3-kinase (PI3K)-α (PIK3CA), another KRAS effector, might cooperate with oncogenic BRAF(V600E) to promote lung cancer progression, we used mice carrying a conditional allele of Pik3ca that allows conversion of the wild-type catalytic subunit of PIK3CA to mutationally activated PIK3CA(H1047R). Although expression of PIK3CA(H1047R) in the lung epithelium, either alone or in combination with PTEN silencing, was without phenotype, concomitant expression of BRAF(V600E) and PIK3CA(H1047R) led to dramatically decreased tumor latency and increased tumor burden compared with BRAF(V600E) alone. Most notably, coexpression of BRAF(V600E) and PIK3CA(H1047R) elicited lung adenocarcinomas in a manner reminiscent of the effects of KRAS(G12D). These data emphasize a role for PI3K signaling, not in lung tumor initiation per se, but in both the rate of tumor growth and the propensity of benign lung tumors to progress to a malignant phenotype. Finally, biologic and biochemical analysis of BRAF(V600E)/PIK3CA(H1047R)-expressing mouse lung cancer cells revealed mechanistic clues about cooperative regulation of the cell-division cycle and apoptosis by these oncogenes.
Endocrine-related Cancer | 2008
Yucheng Wang; Emerick Gallego-Arteche; Gioia Iezza; Xiaochen Yuan; Mary Matli; Su-Pin Choo; Marlene B. Zuraek; Ravi Gogia; Francis C. Lynn; Michael S. German; Emily K. Bergsland; David B. Donner; Robert S. Warren; Eric K. Nakakura
The homeodomain transcription factor NKX2.2 is necessary for neuroendocrine (NE) differentiation in the central nervous system and pancreas. NE tumors derived from the gut are defined by their NE phenotype, which is used for diagnosis and contributes to tumorigenicity. We hypothesized that NKX2.2 is important for NE differentiation in normal and neoplastic gut. NKX2.2 and NE marker expression was investigated in the small intestine of embryonic and adult mice using immunofluorescence (IF). To determine the role of NKX2.2 in NE differentiation of the intestine, the phenotype of Nkx2.2 (-/-) mice was examined by IF and real-time (RT)-PCR. NKX2.2 and NE marker expression in human NE tumors of the gut and normal tissues were evaluated by immunohistochemistry and qRT-PCR. NKX2.2 expression was detected in the intervillus/crypt regions of embryonic and adult mouse intestine. Co-expression of Nkx2.2 with neurogenin3 (NEUROG3) and hormones was observed in the adult intestinal crypt compartment, suggesting NKX2.2 functions in NEUROG3-positive endocrine progenitors and newly differentiated endocrine cells. In the intestine of Nkx2.2 (-/-) mice, we found a dramatic reduction in the number of cells producing numerous hormones, such as serotonin, gastrin, cholecystokinin, somatostatin, glucagon-like peptide 1 (GLP-1), and secretin, but an increase in cells producing ghrelin. NKX2.2 was expressed in most (24 of 29) human NE tumors derived from diverse primary sites. We conclude NKX2.2 functions in immature endocrine cells to control NE differentiation in normal intestine and is expressed in most NE tumors of the gut, and is therefore a novel target of diagnosis for patients with gastrointestinal NE tumors.
Journal of Surgical Research | 2010
Yucheng Wang; Gioia Iezza; Marlene B. Zuraek; David M. Jablons; Pierre Theodore; Emily K. Bergsland; David B. Donner; Robert S. Warren; Eric K. Nakakura
BACKGROUND Patients with neuroendocrine tumors (NETs) may have metastatic disease and unknown primary site. NETs commonly arise from the bronchopulmonary (BP) and gastrointestinal (GI) tract. The largest subgroups of well-differentiated BP-NETs are typical carcinoids (TCs). The homeodomain transcription factor NKX2.2 regulates development of gut serotonin cells and is a marker of GI-NETs. Previous work on a limited number of samples suggested that BP-TCs do not express NKX2.2. We hypothesized that lack of NKX2.2 expression in BP-TCs might be useful to distinguish BP- from GI-NETs, and evaluated NKX2.2 expression in a larger number of BP-TCs. METHODS Archived formalin-fixed, paraffin-embedded tissues were obtained from 13 previously undescribed patients with BP-TCs. Expression of NKX2.2, serotonin, and the NE marker chromogranin A (CgA) were assessed by immunohistochemistry. RESULTS CgA expression was robust in all 13 BP-TCs, confirming the NE phenotype. Serotonin expression was less frequent (9/13; 69%). Two patients with BP-TCs in which serotonin expression was absent exhibited Cushings syndrome due to ectopic ACTH production. NKX2.2 expression was not observed in any of the 13 tumors. CONCLUSIONS Bronchopulmonary TCs uniformly express CgA but not NKX2.2. Because most of these tumors express serotonin, our findings suggest that NKX2.2 may not be required for serotonin production by BP-TCs. We conclude that the presence or absence of NKX2.2 expression may assist in the determination of the primary tumor site in patients with NET metastases of unknown origin. NET metastases that are CgA-positive/NKX2.2-negative would suggest a BP primary, whereas those that are CgA-positive/NKX2.2-positive would suggest a GI primary.
Diagnostic Cytopathology | 2018
Daffolyn Rachael Fels Elliott; Britt-Marie Ljung; Rina Patel; Gioia Iezza
Biceps tendon rupture is generally a clinical and radiographic diagnosis, and only rarely presents to the cytopathologist for fine needle aspiration biopsy. We present a case of ruptured biceps tendon associated with a cystic mass of the upper arm that was diagnosed using fine needle aspiration biopsy, and confirmed with subsequent MRI scan. We describe the clinical presentation, cytomorphology, and immunohistochemical profile of the marked chronic inflammatory infiltrate within the synovial fluid. We also provide a discussion of the differential diagnosis for a cystic mass associated with the biceps tendon on cytology.
Pancreas | 2010
Eric K. Nakakura; Melissa H. Wong; Yucheng Wang; Gioia Iezza; Marlene B. Zuraek; Xiaochen Yuan; David B. Donner; Douglas Hanahan; Robert S. Warren; Emily K. Bergsland
1 Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, CA 94143 2 Department of Pathology, University of California, San Francisco, CA 94143 3 Diabetes Center, University of California, San Francisco, CA 94143 4 Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA 94143 5 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143
American Journal of Otolaryngology | 2006
Ivan H. El-Sayed; David W. Eisele; Tony L. Yang; Gioia Iezza
Thyroid | 2007
Andrew A. Bremer; Brian J. Feldman; Gioia Iezza; Orlo H. Clark; Stephen M. Rosenthal