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Haigis lab reveals metabolic recycling is a crucial source of breast cancer biomass - Oct 19, 2017

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Cancer cells increase nutrient consumption and metabolic fitness to support rapid growth and proliferation. Consequently, the tumor microenvironment (TME) accumulates metabolic by-products, such as lactate and ammonia, which are confined due to poor vascularization of the TME.  In a recent study published in Science, the Haigis lab found that the metabolic by-product ammonia accumulates in the TME of breast cancer xenograft models and has functions far beyond a metabolic waste product.  The authors used stable isotope metabolic tracing studies paired with LC-MS to detect that ammonia liberated in metabolic reactions is recycled and re-incorporated into amino acids.  This recycling enables a cancer cell to maximize the biosynthetic potential of their nitrogen.  Furthermore, the authors found that ammonia was not toxic to breast cancer cells and accelerated their rate of growth and proliferation in vitro and in vivo.  This study re-orients the notion that ammonia is a toxic metabolic by-product, and highlights a novel, biosynthetic function for ammonia in cancer. 

You can read more about this research at Science Daily, Genetic Engineering & Biotechnology News, and HMS News

Wei Mi wins Outstanding Postdoc Award for Cell Biology! - Oct 18, 2017

Wei Mi

Congratulations to Wei Mi, a postdoctoral fellow in the Liao lab, who won the 2017 Outstanding Postdoc Fellow Award for the Department of Cell Biology. Wei's research focuses on understanding the molecular basis of lipid transport between leaflets of a cell's bilayer membrane. Specifically, he is trying to understand how certain membrane proteins, such as flippases, carry out this important cellular function. Currently, Wei is studying MsbA, a flippase found in the membranes of Gram-negative bacteria. Understanding the structure and mechanism of MsbA will be valuable in the design of antibiotics.

New study by Brugge lab uncovers apoptotic vulnerabilities in ovarian cancer - Sep 22, 2017

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High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance; therefore, identification of novel therapies for the treatment of chemotherapy-resistant tumors remains an unmet need. In a recent study published in Nature Communications, the Brugge lab carried out a systematic proteomic profiling analysis of responses to PI3K/mTOR inhibition in 14 HGS-OvCa patient-derived xenografts (PDX) to identify vulnerabilities of chemotherapy-resistant ovarian cancer.  Findings from these studies showed that PI3K/mTOR inhibition strongly promotes apoptotic priming which sensitizes cells to inhibition of BCL2 family anti-apoptotic proteins. Combined inhibition of the PI3K/AKT/mTOR axis and BCL-2/BCL-Xinduces effective tumor cell death in vitro and in orthotopic mouse xenografts in vivo. By performing an in-depth analysis of the BCL-2 family of apoptotic regulators using selective inhibitors and computational modeling, the Brugge lab identified BIM, BCL-XL and MCL-1 as critical players and biomarkers in ovarian cancer cell survival. This study presents a novel systematic approach to comprehensively investigate apoptotic priming mechanisms and identify cell death vulnerabilities in HGS-OvCa.

Bob Farese announced as a 2018 Laureate Award winner by the Endocrine Society - Sep 14, 2017

Bob Farese

Bob Farese has been selected as one of 14 leaders in the endocrinology field to receive a prestigious 2018 Laureate Award from the Endocrine Society. Established in 1944, these awards recognize the highest achievements in the field of endocrinology, including groundbreaking resesarch and innovations in clinical care. Bob was awarded the Roy O. Greep Award for Outstanding Research for his seminal contributions to the understanding of cellular lipid metabolism. His work has shown how alterations in lipid synthesis and storage contribute to the pathogenesis of human diseases, in particular type 2 diabetes, and has suggested new targets for therapy. Bob also pioneered the cell biology of lipid droplets, the cellular organelle responsible for storing triglycerides and metabolic energy, including identifying hundreds of genes that govern lipid storage in cells. To learn more, please click here.

Liao lab uncovers the structural basis for LPS transport by ABC transporter MsbA - Sep 08, 2017

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Lipopolysaccharide (LPS, also known as endotoxin) in Gram-negative bacteria is critical for the bacterial survival and their resistance to antibiotics. As a critical step of LPS biosynthesis, newly produced LPS in the cytoplasmic leaflet of the inner membrane is flipped to the periplasmic leaflet by MsbA, an ATP-binding cassette transporter. In a recent study published in Nature on September 6, the Liao lab use single particle cryo-EM to obtain high-resolution snapshots of MsbA at different functional states. This study uncovers the structural basis for LPS transport, and paves the way for structural characterization of many other lipid flippases.

Finley lab discovers how red blood cells remodel during terminal differentiation - Aug 24, 2017

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The Finley lab, in a recent publication in Science, found that a mutation in the murine Ube2o gene, which encodes an ubiquitin-conjugating enzyme induced during erythropoiesis, results in anemia. Proteomic analysis suggested that UBE2O is a broad-spectrum ubiquitinating enzyme that remodels the erythroid proteome. You can read more about this research in an article here on the HMS news webpage.

Depolymerase mechanism for a length-dependent microtubule regulator defined by Pellman lab - Aug 23, 2017

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Proper establishment of the size of intracellular microtubule-based structures, the mitotic spindle or the cilia, is key for their cellular function. One class of mechanisms mediating size control of these intracellular structures utilizes molecular motors as “measuring devices”.  Kinesin-8 motors have a conserved role in regulating the size of microtubule structures, using length-dependent accumulation at the plus-end to preferentially disassemble long microtubules. Despite extensive study, the kinesin-8 depolymerase mechanism has been debated. In a paper recently published in Developmental Cell, the Pellman lab (with first author Hugo Arellano-Santoyo) defined a tubulin curvature-sensing mechanism for Kip3/kinesin-8 depolymerization. On the straight tubulin of the microtubule lattice, Kip3 behaves like conventional motile kinesin, using ATP for processive stepping, as assayed by single molecule imaging. Upon reaching the curved tubulin of the microtubule plus-end, Kip3 undergoes a switch: Its ATPase activity is suppressed when it binds tightly to the curved conformation of tubulin. This prolongs plus-end binding, stabilizes protofilament curvature, and ultimately promotes microtubule disassembly. This tubulin-binding switch has allowed the co-existence of motility and depolymerase activity in Kip3/kinesin-8s, which is central to their ability to regulate the length of cellular microtubule structures. These findings also illustrate how small scale tuning of binding affinities and rate constants for an enzyme can generate strikingly divergent macroscopic properties.

Farese and Walther lab discovers triglyceride synthesis enzyme DGAT1 protects adipocytes from lipid induced ER stress during lipolysis - Aug 10, 2017

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Triglyceride (TG) storage in adipose tissue provides the major reservoir for metabolic energy in mammals. During lipolysis, fatty acids (FAs) are hydrolyzed from adipocyte TG stores and transported to other tissues for fuel. For unclear reasons, a large portion of hydrolyzed FAs in adipocytes is re-esterified to TGs in a “futile”, ATP-consuming, energy dissipating cycle. The Farese & Walther lab's recent publication in Cell Metabolism shows that FA re-esterification during adipocyte lipolysis is mediated by DGAT1, an ER-localized DGAT enzyme. Surprisingly, this re-esterification cycle does not preserve TG mass, but instead functions to protect the ER from lipotoxic stress and related consequences, such as adipose tissue inflammation. These results reveal an important role for DGAT activity and TG synthesis generally in averting ER stress and lipotoxicity, with specifically DGAT1 performing this function during stimulated lipolysis in adipocytes.

Recent Faculty Promotion: Adrian Salic - Jul 21, 2017

Adrian Salic

Congratulations to Adrian Salic on his promotion to Professor of Cell Biology!

Adrian uses biochemistry, cell, and chemical biology to elucidate how vertebrate cells send and respond to Hedgehog signals. Two key aspects his lab is currently investigating are the activation of the secreted Hedgehog protein and the regulated proteolysis of Gli, the transcriptional effector of the Hedghog pathway.