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Interplay of approximate planning strategies

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2015年第10期112卷 3098-3103页

作者： Huys, Quentin J. M. Lally, Niall Faulkner, Paul Eshel, Neir Seifritz, Erich Gershman, Samuel J. Dayan, Peter Roiser, Jonathan P. Univ Zurich Inst Biomed Engn Translat Neuromodeling Unit CH-8032 Zurich Switzerland Swiss Fed Inst Technol CH-8032 Zurich Switzerland Univ Zurich Hosp Psychiat Dept Psychiat Psychotherapy & Psychosomat CH-8032 Zurich Switzerland UCL Inst Cognit Neurosci London WC1N 3AR England NIMH Expt Therapeut & Pathophysiol Branch Intramural Res Program NIH Bethesda MD 20892 USA Univ Calif Los Angeles Semel Inst Neurosci & Human Behav Los Angeles CA 90095 USA Harvard Univ Sch Med Program Neurosci Boston MA 02115 USA Harvard Univ Sch Med MD PhD Program Boston MA 02115 USA MIT Dept Brain & Cognit Sci Cambridge MA 02139 USA UCL Gatsby Computat Neurosci Unit London WC1N 3AR England

Humans routinely formulate plans in domains so complex that even the most powerful computers are taxed. To do so, they seem to avail themselves of many strategies and heuristics that efficiently simplify, approximate, and hierarchically decompose hard tasks into simpler subtasks. Theoretical and cognitive research has revealed several such strategies;however, little is known about their establishment, interaction, and efficiency. Here, we use model-based behavioral analysis to provide a detailed examination of the performance of human subjects in a moderately deep planning task. We find that subjects exploit the structure of the domain to establish subgoals in a way that achieves a nearly maximal reduction in the cost of computing values of choices, but then combine partial searches with greedy local steps to solve subtasks, and maladaptively prune the decision trees of subtasks in a reflexive manner upon encountering salient losses. Subjects come idiosyncratically to favor particular sequences of actions to achieve subgoals, creating novel complex actions or "options."

关键词： planning hierarchical reinforcement learning memoization pruning

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Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment

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NATURE GENETICS 2022年第8期54卷 1178-+页

作者： Hwang, William L. Jagadeesh, Karthik A. Guo, Jimmy A. Hoffman, Hannah, I Yadollahpour, Payman Reeves, Jason W. Mohan, Rahul Drokhlyansky, Eugene Van Wittenberghe, Nicholas Ashenberg, Orr Farhi, Samouil L. Schapiro, Denis Divakar, Prajan Miller, Eric Zollinger, Daniel R. Eng, George Schenkel, Jason M. Su, Jennifer Shiau, Carina Yu, Patrick Freed-Pastor, William A. Abbondanza, Domenic Mehta, Arnav Gould, Joshua Lambden, Conner Porter, Caroline B. M. Tsankov, Alexander Dionne, Danielle Waldman, Julia Cuoco, Michael S. Lan Nguyen Delorey, Toni Phillips, Devan Barth, Jaimie L. Kem, Marina Rodrigues, Clifton Ciprani, Debora Roldan, Jorge Zelga, Piotr Jorgji, Vjola Chen, Jonathan H. Ely, Zackery Zhao, Daniel Fuhrman, Kit Fropf, Robin Beechem, Joseph M. Loeffler, Jay S. Ryan, David P. Weekes, Colin D. Ferrone, Cristina R. Qadan, Motaz Aryee, Martin J. Jain, Rakesh K. Neuberg, Donna S. Wo, Jennifer Y. Hong, Theodore S. Xavier, Ramnik Aguirre, Andrew J. Rozenblatt-Rosen, Orit Mino-Kenudson, Mari Fernandez-del Castillo, Carlos Liss, Andrew S. Ting, David T. Jacks, Tyler Regev, Aviv Harvard Med Sch Ctr Syst Biol Massachusetts Gen Hosp Boston MA 02115 USA Harvard Med Sch Dept Radiat Oncol Massachusetts Gen Hosp Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA MIT Dept Biol Koch Inst Integrat Canc Res Cambridge MA 02139 USA Univ Calif San Francisco Sch Med San Francisco CA USA Harvard Med Sch Dana Farber Canc Inst Dept Med Oncol Boston MA USA Harvard Med Sch Biol & Biomed Sci Program Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD & Hlth Sci & Technol Program Boston MA 02115 USA NanoString Technol Seattle WA USA Harvard Med Sch Dept Syst Biol Lab Syst Pharmacol Boston MA USA Harvard Med Sch Dept Pathol Massachusetts Gen Hosp Boston MA USA Harvard Med Sch Brigham & Womens Hosp Dept Pathol Boston MA USA Harvard Med Sch Massachusetts Gen Hosp Dept Med Oncol Boston MA USA Harvard Med Sch Massachusetts Gen Hosp Dept Surg Boston MA USA New York Med Coll Valhalla NY 10595 USA Harvard Med Sch Massachusetts Gen Hosp Edwin L Steele Lab Tumor Biol Boston MA USA Dana Farber Canc Inst Dept Data Sci Boston MA USA Heidelberg Univ Inst Computat Biomed Fac Med Heidelberg Germany Heidelberg Univ Inst Pathol Fac Med Heidelberg Germany Heidelberg Univ Hosp Heidelberg Germany Genentech Inc San Francisco CA 94080 USA

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions. Single-nucleus and spatial, whole-transcriptome profiling of 43 pancreatic adenocarcinomas provides a refined molecular and cellular classification, highlighting a new neoadjuvant treatment-associated neural-like progenitor tumor cell state.

关键词： Gene expression Pancreatic cancer Transcriptomics

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Stepwise Nucleosome Translocation by RSC Remodeling Complexes

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BIOPHYSICAL JOURNAL 2016年第3期110卷 515A-515A页

作者： Harada, Bryan T. Hwang, William L. Deindl, Sebastian Bartholomew, Blaine Zhuang, Xiaowei Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA Harvard Univ Grad Program Biophys Cambridge MA 02138 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA USA Univ Texas MD Anderson Canc Ctr Dept Epigenet & Mol Carcinogenesis Smithville TX USA Howard Hughes Med Inst Cambridge MA USA

2539-Plat

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Field-deployable viral diagnostics using CRISPR-Cas13

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SCIENCE 2018年第6387期360卷 444-448页

作者： Myhrvold, Cameron Freije, Catherine A. Gootenberg, Jonathan S. Abudayyeh, Omar O. Metsky, Hayden C. Durbin, Ann F. Kellner, Max J. Tan, Amanda L. Paul, Lauren M. Parham, Leda A. Garcia, Kimberly F. Barnes, Kayla G. Chak, Bridget Mondini, Adriano Nogueira, Mauricio L. Isern, Sharon Michael, Scott F. Lorenzana, Ivette Yozwiak, Nathan L. MacInnis, Bronwyn L. Bosch, Irene Gehrke, Lee Zhang, Feng Sabeti, Pardis C. Broad Inst Massachusetts Inst Technol MIT & Harva Cambridge MA 02142 USA Harvard Univ Dept Organismal & Evolutionary Biol Ctr Syst Biol Cambridge MA 02138 USA Harvard Med Sch Div Med Sci PhD Program Virol Boston MA 02115 USA Harvard Med Sch Dept Syst Biol Boston MA 02115 USA MIT McGovern Inst Brain Res Cambridge MA 02139 USA MIT Dept Brain & Cognit Sci Cambridge MA 02139 USA MIT Dept Biol Engn Cambridge MA 02139 USA MIT Dept Hlth Sci & Technol Cambridge MA 02139 USA MIT Dept Elect Engn & Comp Sci Cambridge MA 02139 USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA Florida Gulf Coast Univ Dept Biol Sci Ft Myers FL 33965 USA Univ Nacl Autonoma Honduras Inst Invest Microbiol Ctr Invest Genet Tegucigalpa Honduras Harvard Sch Publ Hlth Dept Immunol & Infect Dis Boston MA 02115 USA Sao Paulo State Univ Sch Pharmaceut Sci Araraquara Lab Publ Hlth Sao Paulo Brazil Fac Med Sao Jose do Rio Preto Lab Pesquisas Virol Sao Paulo Brazil Mt Sinai Sch Med Dept Med New York NY 10029 USA Harvard Med Sch Dept Microbiol & Immunobiol Boston MA 02115 USA HHMI Chevy Chase MD 20815 USA

mitigating global infectious disease requires diagnostic tools that are sensitive, specific, and rapidly field deployable. In this study, we demonstrate that the Cas13-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) platform can detect Zika virus (ZIKV) and dengue virus (DENV) in patient samples at concentrations as low as 1 copy per microliter. We developed HUDSON (heating unextracted diagnostic samples to obliterate nucleases), a protocol that pairs with SHERLOCK for viral detection directly from bodily fluids, enabling instrument-free DENVdetection directly from patient samples in <2 hours. We further demonstrate that SHERLOCK can distinguish the four DENV serotypes, as well as region-specific strains of ZIKV from the 2015-2016 pandemic. Finally, we report the rapid (<1 week) design and testing of instrument-free assays to detect clinically relevant viral single-nucleotide polymorphisms.

关键词： BIOTECHNOLOGY VIRAL disease diagnosis ZIKA virus infections DIAGNOSIS DENGUE DIAGNOSIS of fever COMMUNICABLE diseases ENZYMOLOGY

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Deployable CRISPR-Cas13a diagnostic tools to detect and report Ebola and Lassa virus cases in real-time

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NATURE COMMUNICATIONS 2020年第1期11卷 1-10页

作者： Barnes, Kayla G. Lachenauer, Anna E. Nitido, Adam Siddiqui, Sameed Gross, Robin Beitzel, Brett Siddle, Katherine J. Freije, Catherine A. Dighero-Kemp, Bonnie Mehta, Samar B. Carter, Amber Uwanibe, Jessica Ajogbasile, Fehintola Olumade, Testimony Odia, Ikponmwosa Sandi, John Demby Momoh, Mambu Metsky, Hayden C. Boehm, Chloe K. Lin, Aaron E. Kemball, Molly Park, Daniel J. Branco, Luis Boisen, Matt Sullivan, Brian Amare, Mihret F. Tiamiyu, Abdulwasiu B. Parker, Zahra F. Iroezindu, Michael Grant, Donald S. Modjarrad, Kayvon Myhrvold, Cameron Garry, Robert F. Palacios, Gustavo Hensley, Lisa E. Schaffner, Stephen F. Happi, Christian T. Colubri, Andres Sabeti, Pardis C. Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Univ Dept Immunol & Infect Dis Harvard TH Chan Sch Publ Hlth Boston MA 02115 USA Univ Glasgow MRC Ctr Virus Res Glasgow Lanark Scotland Stanford Univ Sch Med Stanford CA 94305 USA Ragon Inst MGH MIT & Harvard Cambridge MA 02139 USA Harvard Med Sch Div Med Sci PhD Program Virol Boston MA 02115 USA MIT Computat & Syst Biol 77 Massachusetts Ave Cambridge MA 02139 USA NIAID Integrated Res Facil Div Clin Res NIH Frederick MD USA US Army Ctr Genome Sci Med Res Inst Infect Dis 1425 Porter St Ft Detrick MD 21702 USA Harvard Univ Dept Organism & Evolutionary Biol Ctr Syst Biol Cambridge MA 02138 USA Beth Israel Deaconess Med Ctr Div Infect Dis Boston MA USA Redeemers Univ African Ctr Excellence Genom Infect Dis ACEGID Ede Osun State Nigeria Redeemers Univ Coll Nat Sci Dept Biol Sci Ede Osun State Nigeria Irrua Specialist Teaching Hosp Inst Lassa Fever Res & Control Irrua Edo State Nigeria Kenema Govt Hosp Viral Hemorrhag Fever Program Kenema Sierra Leone MIT Dept Elect Engn & Comp Sci Cambridge MA 02139 USA Zalgen Labs Germantown MD USA Scripps Res Inst Dept Immunol & Microbial Sci La Jolla CA USA Walter Reed Army Inst Res Emerging Infect Dis Branch Silver Spring MD USA Henry M Jackson Fdn Adv Mil Med Bethesda MD USA Henry M Jackson Fdn Med Res Int Abuja Nigeria Minist Hlth & Sanit Freetown Sierra Leone Tulane Univ Sch Med Los Angeles CA 70112 USA Howard Hughes Med Inst Chevy Chase MD USA

Recent outbreaks of viral hemorrhagic fevers (VHFs), including Ebola virus disease (EVD) and Lassa fever (LF), highlight the urgent need for sensitive, deployable tests to diagnose these devastating human diseases. Here we develop CRISPR-Cas13a-based (SHERLOCK) diagnostics targeting Ebola virus (EBOV) and Lassa virus (LASV), with both fluorescent and lateral flow readouts. We demonstrate on laboratory and clinical samples the sensitivity of these assays and the capacity of the SHERLOCK platform to handle virus-specific diagnostic challenges. We perform safety testing to demonstrate the efficacy of our HUDSON protocol in heat-inactivating VHF viruses before SHERLOCK testing, eliminating the need for an extraction. We develop a user-friendly protocol and mobile application (HandLens) to report results, facilitating SHERLOCK's use in endemic regions. Finally, we successfully deploy our tests in Sierra Leone and Nigeria in response to recent outbreaks. Outbreaks of viral hemorrhagic fevers highlight the need for sensitive, field-deployable diagnostics. Here the authors present a CRISPR-based SHERLOCK platform with field protocol and mobile app for Ebola and Lassa fever outbreaks.

关键词： CRISPR-Cas systems Viral infection Virology

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Training a computer-aided polyp detection system to detect sessile serrated adenomas using public domain colonoscopy videos

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ENDOSCOPY INTERNATIONAL OPEN 2020年第10期8卷 E1448-E1454页

作者： Li, Taibo Glissen Brown, Jeremy R. Tsourides, Kelovoulos Mahmud, Nadim Cohen, Jonah M. Berzin, Tyler M. Johns Hopkins Sch Med MD PhD Program Baltimore MD USA MIT Dept Elect Engn & Comp Sci Cambridge MA USA Beth Israel Deaconess Med Ctr Ctr Adv Endoscopy Div Gastroenterol Boston MA USA Harvard Med Sch Boston MA 02130 USA MIT Dept Brain & Cognit Sci Cambridge MA USA Hosp Univ Penn Boston MA USA

Background Colorectal cancer (CRC) is a major public health burden worldwide, and colonoscopy is the most commonly used CRC screening tool. Still, there is variability in adenoma detection rate (ADR) among endoscopists. Recent studies have reported improved ADR using deep learning models trained on videos curated largely from private in-house datasets. Few have focused on the detection of sessile serrated adenomas (SSAs), which are the most challenging target clinically. Methods We identified 23 colonoscopy videos available in the public domain and for which pathology data were provided, totaling 390 minutes of footage. Expert endoscopists annotated segments of video with adenomatous polyps, from which we captured 509 polyp-positive and 6,875 polyp-free frames. Via data augmentation, we generated 15,270 adenomatous polyp-positive images, of which 2,310 were SSAs, and 20,625 polyp-negative images. We used the CNN AlexNet and fine-tuned its parameters using 90% of the images, before testing its performance on the remaining 10% of images unseen by the model. Results We trained the model on 32,305 images and tested performance on 3,590 images with the same proportion of SSA, non-SSA polyp-positive, and polyp-negative images. The overall accuracy of the model was 0.86, with a sensitivity of 0.73 and a specificity of *** predictive value was 0.93 and negative predictive value was *** area under the curve was *** were detected in 93% of SSA-positive images. Conclusions Using a relatively small set of publicly-available colonoscopy data, we obtained sizable training and validation sets of endoscopic images using data augmentation, and achieved an excellent performance in adenomatous polyp detection.

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Imaging Neural Activity Using Thy1-GCaMP Transgenic Mice

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NEURON 2012年第2期76卷 297-308页

作者： Chen, Qian Cichon, Joseph Wang, Wenting Qiu, Li Lee, Seok-Jin R. Campbell, Nolan R. DeStefino, Nicholas Goard, Michael J. Fu, Zhanyan Yasuda, Ryohei Looger, Loren L. Arenkiel, Benjamin R. Gan, Wen-Biao Feng, Guoping MIT Dept Brain & Cognit Sci McGovern Inst Brain Res E25-618 Cambridge MA 02139 USA MIT Dept Brain & Cognit Sci Picower Inst Learning & Memory Cambridge MA 02139 USA NYU Sch Med Dept Physiol & Neurosci Mol Neurobiol ProgramSkirball Inst New York NY 10016 USA Duke Univ Med Ctr Dept Neurobiol Durham NC 27710 USA Duke Univ Med Ctr Dept Psychiat & Behav Sci Durham NC 27710 USA Harvard Univ Sch Med MD PhD Program Boston MA 02115 USA Howard Hughes Med Inst Ashburn VA 20147 USA Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Broad Inst Stanley Ctr Psychiat Res Cambridge MA 02142 USA

The ability to chronically monitor neuronal activity in the living brain is essential for understanding the organization and function of the nervous system. The genetically encoded green fluorescent protein-based calcium sensor GCaMP provides a powerful tool for detecting calcium transients in neuronal somata, processes, and synapses that are triggered by neuronal activities. Here we report the generation and characterization of transgenic mice that express improved GCaMPs in various neuronal subpopulations under the control of the Thy1 promoter. In vitro and in vivo studies show that calcium transients induced by spontaneous and stimulus-evoked neuronal activities can be readily detected at the level of individual cells and synapses in acute brain slices, as well as chronically in awake, behaving animals. These GCaMP transgenic mice allow investigation of activity patterns in defined neuronal populations in the living brain and will greatly facilitate dissecting complex structural and functional relationships of neural networks.

关键词： NEURONS TRANSGENIC mice BRAIN imaging BRAIN function localization GREEN fluorescent protein NEURAL circuitry BRAIN stimulation

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Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development

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ISCIENCE 2020年第3期23卷 100941-100941页

作者： Chu, S. Haihua Chabon, Jonathan R. Matovina, Chloe N. Minehart, Janna C. Chen, Bo-Ruei Zhang, Jian Kumar, Vipul Xiong, Yijun Callen, Elsa Hung, Putzer J. Feng, Zhaohui Koche, Richard P. Liu, X. Shirley Chaudhuri, Jayanta Nussenzweig, Andre Sleckman, Barry P. Armstrong, Scott A. Boston Childrens Hosp Dana Farber Canc Inst Dept Pediat Oncol Div Hematol Oncol 450 Brookline Ave Boston MA 02215 USA NYU Sch Med New York NY USA Weill Cornell Med Coll Dept Pathol & Lab Med New York NY USA Beijing Inst Basic Med Sci Ctr Computat Biol Beijing Peoples R China Dana Farber Canc Inst Dept Biostat & Computat Biol Boston MA 02115 USA Harvard TH Chan Sch Publ Hlth Boston MA USA Harvard Med Sch Howard Hughes Med Inst Dept Pediat Dept Genet Boston MA 02115 USA Harvard Med Sch Harvard Mit MD PhD Program Boston MA 02115 USA NCI Lab Genome Integr NIH Bethesda MD 20892 USA Washington Univ Sch Med Dept Pathol & Immunol St Louis MO USA Mem Sloan Kettering Canc Ctr Canc Biol & Genet 1275 York Ave New York NY 10021 USA Mem Sloan Kettering Canc Ctr Immunol Program New York NY 10021 USA Weill Cornell Grad Sch Med Sci Immunol & Microbial Pathogenesis Program New York NY USA

Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, especially when combined with loss of Atm kinase activity. Furthermore, loss reduces immune repertoire and a severe block in lymphogenesis as well as causes post-mitotic neuronal apoptosis. Together, these studies are suggestive of an important role of Setd2/H3K36me3 in these two mammalian developmental processes that are influenced by double-stranded break repair.

关键词： Biological Sciences Cell Biology Immunology Molecular Biology

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A STUB1 ubiquitin ligase/CHIC2 protein complex negatively regulates the IL-3, IL-5, and GM-CSF cytokine receptor common β chain (CSF2RB) protein stability

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JOURNAL OF BIOLOGICAL CHEMISTRY 2022年第10期298卷 102484页

作者： Koochaki, Sebastian H. J. Slabicki, Mikolaj Lumpkin, Ryan Zou, Charles Belizaire, Roger Fischer, Eric S. Ebert, Benjamin L. Broad Inst MIT & Harvard Cambridge MA 02142 USA Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA Harvard Med Sch Harvard MD PhD Program Boston MA USA Dana Farber Canc Inst Dept Canc Biol Boston MA USA Harvard Med Sch Dept Biol Chem & Mol Pharmacol Boston MA USA Dana Farber Canc Inst Howard Hughes Med Inst Boston MA 02115 USA

The IL-3, IL-5, and GM-CSF family of cytokines play an essential role in the growth, differentiation, and effector functions of multiple hematopoietic cell types. Receptors in this family are composed of cytokine-specific a chains and a common beta chain (CSF2RB), responsible for the majority of downstream signaling. CSF2RB abundance and stability influence the magnitude of the cellular response to cytokine stimulation, but the exact mechanisms of regulation are not well understood. Here, we use genetic screens in multiple cellular contexts and cytokine conditions to identify STUB1, an E3 ubiquitin ligase, and CHIC2 as regulators of CSF2RB ubiq-uitination and protein stability. We demonstrate that Stub1 and Chic2 form a complex that binds Csf2rb and that genetic inactivation of either Stub1 or Chic2 leads to reduced ubiq-uitination of Csf2rb. The effects of Stub1 and Chic2 on Csf2rb were greatest at reduced cytokine concentrations, suggesting that Stub1/Chic2-mediated regulation of Csf2rb is a mechanism of reducing cell surface accumulation when cytokine levels are low. Our study uncovers a mechanism of CSF2RB regulation through ubiquitination and lysosomal degradation and describes a role for CHIC2 in the regulation of a cytokine receptor.

关键词： STUB1 CHIC2 CSF2RB protein degradation ubiquitin cell surface receptor IL-3 cytokine

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Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited

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NATURE METABOLISM 2022年第6期4卷 711-+页

作者： Li, Zhaoqi Ji, Brian W. Dixit, Purushottam D. Tchourine, Konstantine Lien, Evan C. Hosios, Aaron M. Abbott, Keene L. Rutter, Justine C. Westermark, Anna M. Gorodetsky, Elizabeth F. Sullivan, Lucas B. Vander Heiden, Matthew G. Vitkup, Dennis MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol Cambridge MA 02139 USA Columbia Univ Dept Syst Biol New York NY 10027 USA Univ Calif San Diego Dept Med Phys Scientist Training Pathway San Diego CA 92103 USA Univ Florida Dept Phys Gainesville FL 32611 USA Univ Florida Univ Florida Genet Inst Gainesville FL USA Univ Florida Dept Chem Engn Gainesville FL 32611 USA Univ Florida Univ Florida Canc Ctr Gainesville FL USA Harvard Med Sch Hlth Sci & Technol HST Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Fred Hutchinson Canc Res Ctr Human Biol Div 1124 Columbia St Seattle WA 98104 USA Dana Farber Canc Inst Boston MA 02115 USA Columbia Univ Dept Biomed Informat New York NY 10027 USA

Production of oxidized biomass, which requires regeneration of the cofactor NAD(+), can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD(+) deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD(+) consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD(+) is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD(+) availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD(+) consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia. Production of oxidized biomass is necessary to support cancer cell proliferation. In this work, Li et al. provide a quantitative analysis of the cellular needs and biochemical bottlenecks in lipid biosynthesis arising from the requirement to regenerate the cofactor NAD(+).

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