This past week we received our official notice of award for our R01 submission to the NIH/NIDDK! The lab is excited to study 'The role of NCOA4-mediated ferritinophagy in iron homeostasis and ferroptosis.'  From our project summary:

 Specific Aim 1 will define the biochemical mechanisms regulating NCOA4 activity in cells using an integrated quantitative proteomic and cell biologic experimentation workflow. In specific aim 2, we will determine the temporal and spatial dependency of ferritinophagy in vivo for regulating systemic iron homeostasis and erythropoiesis using novel mouse models of NCOA4 knockout and over-expression. Finally, specific aim 3 will focus on examining a role for NCOA4 in regulating sensitivity to ferroptosis in vivo under pathophysiologic conditions, including pancreatic cancer. Together, the proposed in vitro and in vivo studies will identify fundamental roles of NCOA4 in sensing and responding to iron deficiency and overload and determine the utility of pursuing NCOA4 as a therapeutic target for multiple iron-related disorders.

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Our first bioRxiv pre-print! KRASG12C inhibitors are now in clinical trials for oncogenic KRASG12C-driven tumors including Pancreatic Cancer and Lung Cancer and patients are showing responses. As one concern based on experience with other targeted therapies is development of resistance, we modeled development of adaptation/resistance to KRASG12C pharmacologic inhibition and used mass-spectrometry-based quantitative temporal proteomics to understand how adaptation to these inhibitors could develop over time. We next used this proteomic information to design and test drug combinations to enhance response to KRASG12C monotherapy. Combinations with CDK4/6i and HSP90i showed promise but would require further extensive pre-clinical testing to validate. All of our quantitative temporal proteomic data is available via an interactive website:
​ https://manciaslab.shinyapps.io/KRASi/.

​We’re excited to get feedback via the pre-print process! Great work from co-first authors Naiara Santana-Codina and Amrita Singh Chandhoke! Thanks to collaborators, Drs. Nathanael Gray, Wojciech Fendler and Andy Aguirre. 

Naiara Santana-Codina presents work from the lab at the 2019 AACR Pancreatic Cancer: Advances in Science and Clinical Care meeting on using quantitative temporal proteomics to identify combinatorial treatment strategies in Pancreatic Cancer. Great work Naiara!

Interaction proteomics of RABL3 wild-type and mutant: a Integrated interaction map of the RABL3 and RABL3_p.Ser36* network showing high-confidence candidate interacting proteins. Thickness of RABL3 (black) and RABL3_p.Ser36* (red) arrows denotes NWD scores. RAP1GDS1 interactors identified by AP–MS with RAP1GDS1-tagged bait are grouped by protein family for clarity and denoted by dashed gray lines. b, RAP1GDS1 bait-normalized APSMs for RABL3 versus RABL3_p.Ser36* AP–MS. Graph represents mean ± s.d., independent biological replicates N = 3 for RABL3_p.Ser36*, N = 4 for RABL3. **P = 0.0014 by unpaired two-tailed t-test (t = 7.813, d.f. = 4) 

Sahar Nissim from Wolfram Goessling's Lab leads a study identifying a mutation in RABL3 that is associated with hereditary pancreatic ductal adenocarcinoma. Joe initially helped Sahar to identify the molecular mechanism of RABL3 by performing interaction proteomics of RABL3 and RABL3 mutants. To the left is some of the data from the proteomics. Great work from Sahar - this study now nominates RABL3 as a target for genetic testing in cancer families 

Another successful lab BBQ! 

Joe gives a talk to the Boston/Harvard Cell Death Initiative group on the role of NCOA4-mediated ferritinophagy in iron metabolism and ferroptosis.

The lab is excited to welcome Huan Zhang, PhD to the lab! Huan completed her graduate work at the Institute of Microbiology, Chinese Academy of Sciences. Her graduate work was focused on evolution of transcriptional regulatory networks of phytopathogenic bacteria and bacterial resistance to osmostress. She identified and co-first authored a manuscript in Nature Communications on: Proteolysis of histidine kinase VgrS sequesters two-component signalling and promotes bacterial resistance to osmostress. We're excited for her to transition to work on pancreatic cancer and leverage her expertise in RNA biology towards new projects in the lab investigating the role of RNA binding proteins in pancreatic cancer.

Joe runs in the 11th annual Damon Runyon 5K at Yankee Stadium on Saturday, May 11, 2019!

Text from Damon Runyon: 
"More than 2,100 runners, walkers, cancer survivors, and their friends and family members gathered at Yankee Stadium to raise funds for cancer research.  One of New York’s most unique fundraising events, the Runyon 5K is the only charitable run/walk that uses the iconic Stadium as its course.  100% of donations raised by Runyon 5K participants will directly support innovative young scientists funded by the Damon Runyon Cancer Research Foundation.  Since inception, the event has raised more than $5.6 million." 
https://www.damonrunyon.org/get-involved/events