Blog Posts - Mancias Lab - Pancreatic Cancer Research

Clara Poupault joins the lab!

9/21/2020

Clara Poupault joins the lab today as a Research Technician! Clara just graduated from University of Massachusetts Boston with a BS in Biology (Honors). During her undergraduate studies, she worked for 3 years in the lab of Dr. Rister studying Vitamin A deprivation as a novel approach to identify neuroprotective molecules in a Drosophila model. Clara is interested in pursuing a MD-PhD program in the future. We're excited for Clara to begin working in the lab on projects related to radiation resistance and pancreatic cancer biology.

Welcome to the lab Kristen John!

7/7/2020

Kristen John joins us as a research technician today! Welcome to the lab Kristen! Kristen just graduated from Hofstra University after majoring in Cell and Molecular Biology with a minor in Biochemistry. She previously worked in the lab of Jason Sheltzer, PhD at Cold Spring Harbor Laboratory using CRISPR/Cas9 to identify the correct molecular target of previously mischaracterized anti-cancer drugs and is a co-author on a paper published in Science Translational Medicine describing this work. We'er excited for Kristen to join us and help with projects in the lab on understanding resistance to radiation therapy using CRISPR/Cas9 screening.

Welcome to the lab Callum Malcolm!

6/1/2020

The lab welcomes Callum Malcolm to the lab as a Research Technician! Despite the ongoing pandemic, Callum finished up his undergraduate studies with a BSc with Honors from the University of Aberdeen (in Scotland!) and joins the Mancias Lab today to work on NCOA4 iron metabolism related projects.

New lab publication in Cell Reports on 'Defining and Targeting Adaptations to Oncogenic KRAS-G12C Inhibition Using Quantitative Temporal Proteomics'

3/31/2020

In this study published in Cell Reports and led by co-first authors Naiara Santana-Codina, PhD and Amrita Singh Chandhoke, PhD, the lab uses a quantitative temporal proteomics workflow to identify proteomic adaptations to short and long-term KRAS-G12C inhibition (KRASi) in lung and pancreatic adenocarcinoma.

In this study, we quantified 10,805 proteins, representing the most comprehensive KRASi proteome (https://manciaslab.shinyapps.io/KRASi/). Our data reveal common mechanisms of acute and long-term response between KRASG12C-driven tumors. Based on these proteomic data, we identify potent combinations of KRASi with phosphatidylinositol 3-kinase (PI3K), HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using quantitative temporal proteomics, we comprehensively characterize adaptations to KRASi and identify combinatorial regimens with potential therapeutic utility.

Mancias Lab is awarded a R01 from the NIH/NIDDK!

3/1/2020

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.

Funded post-doctoral position available in the Mancias Lab

2/26/2020

A funded postdoctoral fellow position is available in our lab. This is a great opportunity to study pancreatic cancer biology in our group. We have ongoing projects in: selective autophagy, therapeutic resistance, and radiation-induced immune responses. Please see the link for the full job description: https://careers-dfci.icims.com/jobs/18785/research-fellow/job?mode=view&mobile=false&width=783&height=500&bga=true&needsRedirect=false&jan1offset=-300&jun1offset=-240

Our first bioRxiv pre-print: Defining and targeting adaptations to oncogenic KRASG12C inhibition using quantitative temporal proteomics

9/14/2019

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 a poster at the 2019 AACR Pancreatic Cancer: Advances in Science and Clinical Care

9/8/2019

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!

Collaboration with Sahar Nissim and Goessling Lab published in Nature Genetics: Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer

8/12/2019

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

Annual Mancias Lab BBQ!

8/2/2019

Another successful lab BBQ!