Person: Mancias, Joseph
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Mancias
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Joseph
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Mancias, Joseph
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Publication Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy(2014) Mancias, Joseph; Wang, Xiaoxu; Gygi, Steven; Harper, J. Wade; Kimmelman, Alec C.Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration1,2. Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo including organelles, proteins, or intracellular pathogens are targeted for selective autophagy is limited3. We employed quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins, including cargo receptors. Like known cargo receptors, NCOA4 was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species4 but is degraded via autophagy to release iron5,6 through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin leads to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy) critical for iron homeostasis and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.Publication Stereotactic Body Radiotherapy (SBRT) for Intrahepatic and Hilar Cholangiocarcinoma(Ivyspring International Publisher, 2015) Mahadevan, Anand; Dagoglu, Nergiz; Mancias, Joseph; Raven, Kristin; Khwaja, Khalid; Tseng, Jennifer F; Ng, Kimmie; Enzinger, Peter; Miksad, Rebecca; Bullock, Andrea; Evenson, AmyBackground: Unresectable intrahepatic and hilar cholangiocarcinomas carry a dismal prognosis. Systemic chemotherapy and conventional external beam radiation and brachytherapy have been used with limited success. We explored the use of stereotactic body radiotherapy (SBRT) for these patients. Methods: Patients with unresectable intrahepatic or hilar cholangiocarcinoma or those with positive margins were included in this study. Systemic therapy was used at the discretion of the medical oncologist. The CyberknifeTM stereotactic body radiotherapy system used to treat these patients. Patients were treated with three daily fractions. Clinical and radiological follow-up were performed every three months. Results: 34 patients (16 male and 18 female) with 42 lesions were included in this study. There were 32 unresectable tumors and two patients with resected tumors with positive margins. The median SBRT dose was 30Gy in three fractions. The median follow-up was 38 months (range 8-71 months). The actuarial local control rate was 79%. The median overall survival was 17 months and the median progression free survival was ten months. There were four Grade III toxicities (12%), including duodenal ulceration, cholangitis and liver abscess. Conclusions: SBRT is an effective and reasonably safe local therapy option for unresectable intrahepatic or hilar cholangiocarcinoma.Publication Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis(eLife Sciences Publications, Ltd, 2015) Mancias, Joseph; Pontano Vaites, Laura; Nissim, Sahar; Biancur, Douglas E; Kim, Andrew J; Wang, Xiaoxu; Liu, Yu; Goessling, Wolfram; Kimmelman, Alec C; Harper, J WadeNCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4-FTH1 interaction, we demonstrate that direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes. Moreover, NCOA4 abundance is under dual control via autophagy and the ubiquitin proteasome system. Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. In zebrafish and cultured cells, NCOA4 plays an essential role in erythroid differentiation. This work reveals the molecular nature of the NCOA4-ferritin complex and explains how intracellular iron levels modulate NCOA4-mediated ferritinophagy in cells and in an iron-dependent physiological setting. DOI: http://dx.doi.org/10.7554/eLife.10308.001Publication Targeting Autophagy Addiction in Cancer(Impact Journals LLC, 2011) Mancias, Joseph; Kimmelman, Alec C.Autophagy inhibition is a novel cancer therapeutic strategy in the early stages of clinical trial testing. The initial rationale for using autophagy inhibition was generated by research revealing that autophagy is upregulated in response to external stresses, including chemotherapy and radiotherapy. Combining autophagy inhibition with agents that induce autophagy as a pro-survival response may therefore increase their therapeutic efficacy. Recent research has shown that some cancer cells, particularly those driven by the K-Ras oncogene, also depend on elevated levels of autophagy for survival even in the absence of external stressors. In multiple in vitro as well as in vivo systems, oncogenic Ras-mediated transformation and tumor growth are dependent on autophagy to evade metabolic stress and cell death. These studies have subsequently led to further early phase clinical testing whether autophagy inhibition is a viable and effective strategy for targeting Ras-driven tumors. Even before the clinical results are available from these ongoing clinical trials, much work remains to optimally develop the approach of autophagy inhibition clinically; most notably reliably detecting levels of autophagy in human tumor samples, pharmacodynamics of currently available autophagy inhibitors (chloroquine and the derivative hydroxychloroquine), and new target identification and drug development.