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Ludwig 2016 Updates The Ludwig Center for Molecular Oncology at MIT is focused on the processes associated with malignant progression, specifically on the mechanisms that allow cancer cells originating in primary tumors to disseminate and ultimately form metastatic colonies. This multi-step process involves a series of cell-biological and biochemical changes in malignant cells, which are being investigated at several levels. Our research includes the biological determinants that allow disseminated cancer cells to gain a foothold in foreign tissue microenvironments, where they can succeed in spawning rapidly growing metastatic colonies. The Ludwig Center for Molecular Oncology at MIT continues to support the research of Koch Institute faculty members with work focused on the critical problems of cancer progression and metastasis. These include Drs. Weinberg and Jacks who serve as co-leaders of the Center. Drs. Bhatia, Gertler, Hemann, Hynes, Lees, Manalis, Regev and Vander Heiden join them. To note, Dr. Manalis was awarded full membership this year after two years of Pilot Project funding. Following are some structural highlights from the year:

• The annual Ludwig Center for Molecular Oncology at MIT Retreat was held at MIT’s Endicott House on May 24,

2016. This is an outstanding opportunity for Ludwig Center PIs and researchers to share updates, future directions and opportunities for collaborations through scientific presentations and a poster session; over 75 were in attendance.

• Ludwig Center for Molecular Oncology at MIT PIs met quarterly throughout the year. PIs discuss ongoing

research at meetings. There are also multiple opportunities for research discussions available at the Koch Institute at MIT including weekly “floor meetings” and “Friday Focus”.

• Ludwig Graduate Fellowships were awarded to five graduate students. • Ludwig Center Postdoctoral Fellowships were awarded to eight postdoctoral associates. Most importantly is the research that comes from Ludwig Center Membership as demonstrated in the following Member publications from 2016:

• Jain PK, Ramanan V, Schepers AG, Dalvie NS, Panda A, Fleming HE, Bhatia SN. Development of Light-Activated CRISPR Using Guide RNAs with Photocleavable Protectors. Angew Chem Int Ed Engl, 55:12440-12444, 2016. PMID27554600; N/A; 10.1002/anie.201606123

• Miller CL, Muthupalani S, Shen Z, Drees F, Ge Z, Feng Y, Chen X, Gong G, Nagar KK, Wang TC, Gertler FB, Fox JG. Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma. PLoS One, 11:e0152940, 2016. PMID27045955; PMC4821566; 10.1371/journal.pone.0152940

• McConnell RE, Edward van Veen J, Vidaki M, Kwiatkowski AV, Meyer AS, Gertler FB. A requirement for filopodia extension toward Slit during Robo-mediated axon repulsion. J Cell Biol, 213:261-274, 2016. PMID27091449; PMC5084274; 10.1083/jcb.201509062

• Rajadurai CV, Havrylov S, Coelho PP, Ratcliffe CD, Zaoui K, Huang BH, Monast A, Chughtai N, Sangwan V, Gertler FB, Siegel PM, Park M. 5'-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion. J Cell Biol, 214:719-734, 2016. PMID27597754; PMC5021089; 10.1083/jcb.201501003

• Weidmann MD, Surve CR, Eddy RJ, Chen X, Gertler FB, Sharma VP, Condeelis JS. MenaINV dysregulates cortactin phosphorylation to promote invadopodium maturation. Sci Rep, 6:36142, 2016. PMID27824079; PMC5099927; 10.1038/srep36142

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• Oudin MJ, Jonas O, Kosciuk T, Broye LC, Guido BC, Wyckoff J, Riquelme D, Lamar JM, Asokan SB, Whittaker C, Ma D, Langer R, Cima MJ, Wisinski KB, Hynes RO, Lauffenburger DA, Keely PJ, Bear JE, Gertler FB. Tumor cell-driven extracellular matrix remodeling enables haptotaxis during metastatic progression. Cancer Discov, 6:516-531, 2016. PMID26811325; PMC4854754; 10.1158/2159-8290.CD-15-1183

• Gordonov S, Hwang MK, Wells A, Gertler FB, Lauffenburger DA, Bathe M. Time series modeling of live-cell shape dynamics for image-based phenotypic profiling. Integr Biol (Camb), 8:73-90, 2016. PMID26658688; PMC5058786; 10.1039/c5ib00283d

• Oudin MJ, Hughes SK, Rohani N, Moufarrej MN, Jones JG, Condeelis JS, Lauffenburger DA, Gertler FB. Characterization of the expression of the pro-metastatic Mena isoform during breast tumor progression. Clin Exp Metastasis, 33:249-261, 2016. PMID26680363; PMC4777680; 10.1007/s10585-015-9775-5

• Oudin MJ, Miller MA, Klazen JA, Kosciuk T, Lussiez A, Hughes SK, Tadros J, Bear JE, Lauffenburger DA, Gertler FB. MenaINV mediates synergistic crosstalk between signaling pathways driving chemotaxis and haptotaxis. Mol Biol Cell, 27:3085-3094, 2016. PMID27559126; PMC5063616; 10.1091/mbc.E16-04-0212

• Balsamo M, Mondal C, Carmona G, McClain LM, Riquelme DN, Tadros J, Ma D, Vasile E, Condeelis JS, Lauffenburger DA, Gertler FB. The alternatively-included 11a sequence modifies the effects of Mena on actin cytoskeletal organization and cell behavior. Sci Rep, 6:35298, 2016. PMID27748415; PMC5066228; 10.1038/srep35298

• Miller MA, Oudin MJ, Sullivan RJ, Wang SJ, Meyer AS, Im H, Frederick DT, Tadros J, Griffith LG, Lee H, Weissleder R, Flaherty KT, Gertler FB, Lauffenburger DA. Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance. Cancer Discov, 6:382-399, 2016. PMID26984351; PMC5087317; 10.1158/2159-8290.CD-15-0933

• Boodram JN, Mcgregor IJ, Bruno PM, Cressey PB, Hemann MT, Suntharalingam K. Breast Cancer Stem Cell Potent Copper(II)-Non-Steroidal Anti-Inflammatory Drug Complexes. Angew Chem Int Ed Engl, 55:2845-2850, 2016. PMID26806362; N/A; 10.1002/anie.201510443

• Braun CJ, Bruno PM, Horlbeck MA, Gilbert LA, Weissman JS, Hemann MT. Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation. Proc Natl Acad Sci U S A, 113:E3892-E3900, 2016. PMID27325776; PMC4941480; 10.1073/pnas.1600582113

• Bent EH, Gilbert LA, Hemann MT. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev, 30:1811-1821, 2016. PMID27566778; PMC5024680; 10.1101/gad.284851.116

• Wilson JL, Dalin S, Gosline S, Hemann M, Fraenkel E, Lauffenburger DA. Pathway-based network modeling finds hidden genes in shRNA screen for regulators of acute lymphoblastic leukemia. Integr Biol (Camb), 8:761-774, 2016. PMID27315426; PMC5224708; 10.1039/c6ib00040a

• Sun D, Dalin S, Hemann MT, Lauffenburger DA, Zhao B. Differential selective pressure alters rate of drug resistance acquisition in heterogeneous tumor populations. Sci Rep, 6:36198, 2016. PMID27819268; PMC5098152; 10.1038/srep36198

• Zhao B, Hemann MT, Lauffenburger DA. Modeling Tumor Clonal Evolution for Drug Combinations Design. Trends Cancer, 2:144-158, 2016. PMID28435907; PMC5400294; 10.1016/j.trecan.2016.02.001

• Naba A, Clauser KR, Ding H, Whittaker CA, Carr SA, Hynes RO. The Extracellular Matrix: Tools and Insights for the "Omics" Era. Matrix Biol, 49:10-24, 2016. PMID26163349; PMC5013529; 10.1016/j.matbio.2015.06.003

• Chen MB, Lamar JM, Li R, Hynes RO, Kamm RD. Elucidation of the roles of tumor integrin ss1 in the extravasation stage of the metastasis cascade. Cancer Res, 76:2513-2524, 2016. PMID26988988; PMC4873393; 10.1158/0008-5472.CAN-15-1325

• Pucci F, Rickelt S, Newton AP, Garris C, Nunes E, Evavold C, Pfirschke C, Engblom C, Mino-Kenudson M, Hynes RO, Weissleder R, Pittet MJ. PF4 Promotes Platelet Production and Lung Cancer Growth. Cell Rep, 17:1764-1772, 2016. PMID27829148; PMC5108525; 10.1016/j.celrep.2016.10.031

• Dimitrova N, Gocheva V, Bhutkar A, Resnick R, Jong RM, Miller KM, Bendor J, Jacks T. Stromal expression of miR-143/145 promotes neoangiogenesis in lung cancer development. Cancer Discov, 6:188-201, 2016. PMID26586766; PMC4744583; 10.1158/2159-8290.CD-15-0854

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• Masri S, Papagiannakopoulos T, Kinouchi K, Liu Y, Cervantes M, Baldi P, Jacks T, Sassone-Corsi P. Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis. Cell, 165:896-909, 2016. PMID27153497; PMC5373476; 10.1016/j.cell.2016.04.039

• Muzumdar MD, Dorans KJ, Chung KM, Robbins R, Tammela T, Gocheva V, Li CM, Jacks T. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat Commun, 7:12685, 2016. PMID27585860; PMC5025814; 10.1038/ncomms12685

• McFadden DG, Politi K, Bhutkar A, Chen FK, Song X, Pirun M, Santiago PM, Kim-Kiselak C, Platt JT, Lee E, Hodges E, Rosebrock AP, Bronson RT, Socci ND, Hannon GJ, Jacks T, Varmus H. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc Natl Acad Sci U S A, 113:E6409-E6417, 2016. PMID27702896; PMC5081629; 10.1073/pnas.1613601113

• Dixit A, Parnas O, Li B, Chen J, Fulco CP, Jerby-Arnon L, Marjanovic ND, Dionne D, Burks T, Raychowdhury R, Adamson B, Norman TM, Lander ES, Weissman JS, Friedman N, Regev A. Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens. Cell, 167:1853-1866.e17, 2016. PMID27984732; PMC5181115; 10.1016/j.cell.2016.11.038

• Ferretti R, Bhutkar A, McNamara MC, Lees JA. BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance. Genes Dev, 30:18-33, 2016. PMID26679841; PMC4701976; 10.1101/gad.267757.115

• Cermak N, Olcum S, Delgado FF, Wasserman SC, Payer KR, A Murakami M, Knudsen SM, Kimmerling RJ, Stevens MM, Kikuchi Y, Sandikci A, Ogawa M, Agache V, Baleras F, Weinstock DM, Manalis SR. High-throughput measurement of single-cell growth rates using serial microfluidic mass sensor arrays. Nat Biotechnol, 34:1052-1059, 2016. PMID27598230; PMC5064867; 10.1038/nbt.3666

• Stevens MM, Maire CL, Chou N, Murakami MA, Knoff DS, Kikuchi Y, Kimmerling RJ, Liu H, Haidar S, Calistri NL, Cermak N, Olcum S, Cordero NA, Idbaih A, Wen PY, Weinstock DM, Ligon KL, Manalis SR. Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate. Nat Biotechnol, 34:1161-1167, 2016. PMID27723727; PMC5142231; 10.1038/nbt.3697

• Kimmerling RJ, Lee Szeto G, Li JW, Genshaft AS, Kazer SW, Payer KR, de Riba Borrajo J, Blainey PC, Irvine DJ, Shalek AK, Manalis SR. A microfluidic platform enabling single-cell RNA-seq of multigenerational lineages. Nat Commun, 7:10220, 2016. PMID26732280; PMC4729820; 10.1038/ncomms10220

• Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller PG, McConkey M, Tothova Z, Tejero H, Heckl D, Jaras M, Chen MC, Li H, Tamayo A, Cowley GS, Rozenblatt-Rosen O, Al-Shahrour F, Regev A, Ebert BL. Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML. Cell, 165:303-316, 2016. PMID27058663; PMC4826477; 10.1016/j.cell.2016.03.015

• Tirosh I, Izar B, Prakadan SM, Wadsworth MH2nd, Treacy D, Trombetta JJ, Rotem A, Rodman C, Lian C, Murphy G, Fallahi-Sichani M, Dutton-Regester K, Lin JR, Cohen O, Shah P, Lu D, Genshaft AS, Hughes TK, Ziegler CG, Kazer SW, Gaillard A, Kolb KE, Villani AC, Johannessen CM, Andreev AY, Van Allen EM, Bertagnolli M, Sorger PK, Sullivan RJ, Flaherty KT, Frederick DT, Jane-Valbuena J, Yoon CH, Rozenblatt-Rosen O, Shalek AK, Regev A, Garraway LA. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science, 352:189-196, 2016. PMID27124452; PMC4944528; 10.1126/science.aad0501

• Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, Neftel C, Desai N, Nyman J, Izar B, Luo CC, Francis JM, Patel AA, Onozato ML, Riggi N, Livak KJ, Gennert D, Satija R, Nahed BV, Curry WT, Martuza RL, Mylvaganam R, Iafrate AJ, Frosch MP, Golub TR, Rivera MN, Getz G, Rozenblatt-Rosen O, Cahill DP, Monje M, Bernstein BE, Louis DN, Regev A, Suva ML. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature, 539:309-313, 2016. PMID27806376; PMC5465819; 10.1038/nature20123

• Yuan C, Clish CB, Wu C, Mayers JR, Kraft P, Townsend MK, Zhang M, Tworoger SS, Bao Y, Qian ZR, Rubinson DA, Ng K, Giovannucci EL, Ogino S, Stampfer MJ, Gaziano JM, Ma J, Sesso HD, Anderson GL, Cochrane BB, Manson JE, Torrence ME, Kimmelman AC, Amundadottir LT, Vander Heiden MG, Fuchs CS, Wolpin BM. Circulating Metabolites and Survival Among Patients With Pancreatic Cancer. J Natl Cancer Inst, 108:djv409, 2016. PMID26755275; PMC4849356; 10.1093/jnci/djv409

• Mattaini KR, Sullivan MR, Vander Heiden MG. The importance of serine metabolism in cancer. J Cell Biol, 214:249-257, 2016. PMID27458133; PMC4970329; 10.1083/jcb.201604085

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• Keibler MA, Wasylenko TM, Kelleher JK, Iliopoulos O, Vander Heiden MG, Stephanopoulos G. Metabolic requirements for cancer cell proliferation. Cancer Metab, 4:16, 2016. PMID27540483; PMC4989334; 10.1186/s40170-016-0156-6

• Gui DY, Sullivan LB, Luengo A, Hosios AM, Bush LN, Gitego N, Davidson SM, Freinkman E, Thomas CJ, Vander Heiden MG. Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. Cell Metab, 24:716-727, 2016. PMID27746050; PMC5102768; 10.1016/j.cmet.2016.09.006

• Abou-Alfa GK, Andersen JB, Chapman W, Choti M, Forbes SJ, Gores GJ, Hong TS, Harding JJ, Vander Heiden MG, Javle M, Kelley RK, Kwong LN, Lowery M, Merrell A, Miyabe K, Rhim A, Saha S, Sia D, Tanasanvimon S, Venook A, Valle JW, Walesky C, Whetstine J, Willenbring H, Zhu AX, Mayer D, Stanger BZ. Advances in cholangiocarcinoma research: report from the third Cholangiocarcinoma Foundation Annual Conference. J Gastrointest Oncol, 7:819-827, 2016. PMID28078106; PMC5177567; 10.21037/jgo.2016.11.11

• Pikman Y, Puissant A, Alexe G, Furman A, Chen LM, Frumm SM, Ross L, Fenouille N, Bassil CF, Lewis CA, Ramos A, Gould J, Stone RM, DeAngelo DJ, Galinsky I, Clish CB, Kung AL, Hemann MT, Vander Heiden MG, Banerji V, Stegmaier K. Targeting MTHFD2 in acute myeloid leukemia. J Exp Med, 213:1285-1306, 2016. PMID27325891; PMC4925018; 10.1084/jem.20151574

• Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA, Luengo A, Bauer MR, Jha AK, O'Brien JP, Pierce KA, Gui DY, Sullivan LB, Wasylenko TM, Subbaraj L, Chin CR, Stephanopolous G, Mott BT, Jacks T, Clish CB, Vander Heiden MG. Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer. Cell Metab, 23:517-528, 2016. PMID26853747; PMC4785096; 10.1016/j.cmet.2016.01.007

• Dayton TL, Gocheva V, Miller KM, Israelsen WJ, Bhutkar A, Clish CB, Davidson SM, Luengo A, Bronson RT, Jacks T, Vander Heiden MG. Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma. Genes Dev, 30:1020-1033, 2016. PMID27125672; PMC4863734; 10.1101/gad.278549.116

• Papagiannakopoulos T, Bauer MR, Davidson SM, Heimann M, Subbaraj L, Bhutkar A, Bartlebaugh J, Vander Heiden MG, Jacks T. Circadian Rhythm Disruption Promotes Lung Tumorigenesis. Cell Metab, 24:324-331, 2016. PMID27476975; PMC5367626; 10.1016/j.cmet.2016.07.001

• Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, Bauer MR, Lau AN, Ji BW, Dixit PD, Hosios AM, Muir A, Chin CR, Freinkman E, Jacks T, Wolpin BM, Vitkup D, Vander Heiden MG. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science, 353:1161-1165, 2016. PMID27609895; PMC5245791; 10.1126/science.aaf5171

• Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA, Zill C, Reinhardt F, Tam WL, Weinberg RA. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science, 351:aad3680, 2016. PMID26941323; PMC5131720; 10.1126/science.aad3680

• Spiegel A, Brooks MW, Houshyar S, Reinhardt F, Ardolino M, Fessler E, Chen MB, Krall JA, DeCock J, Zervantonakis IK, Iannello A, Iwamoto Y, Cortez-Retamozo V, Kamm RD, Pittet MJ, Raulet DH, Weinberg RA. Neutrophils suppress intraluminal NK-mediated tumor cell clearance and enhance extravasation of disseminated carcinoma cells. Cancer Discov, 6:630-649, 2016. PMID27072748; PMC4918202; 10.1158/2159-8290.CD-15-1157

• De Cock JM, Shibue T, Dongre A, Keckesova Z, Reinhardt F, Weinberg RA. Inflammation triggers Zeb1-dependent escape from tumor latency. Cancer Res, 76:6778-6784, 2016. PMID27530323; PMC5135644; 10.1158/0008-5472.CAN-16-0608

• Chaffer CL, San Juan BP, Lim E, Weinberg RA. EMT, cell plasticity and metastasis. Cancer Metastasis Rev, 35:645-654, 2016. PMID27878502; N/A; 10.1007/s10555-016-9648-7

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Expenditures Use of Ludwig Center for Molecular Oncology at MIT funds are focused on Faculty Research including direct support for research through use of the Koch Institute Swanson Biotechnology Center Core Facilities, Pilot Projects to support novel research projects and fellowships for graduate students and postdoctoral associates. Support for the Ludwig Center in 2016 was broken down as indicated in the chart below.

62%

3%4%

15%

6% 10%

LudwigCenterforMolecularOncologyatMIT

2016Expenditures

FacultyResearch

PilotProjects

AdministrativeSupport

CoreFacilities

GraduateFellowships

PostdoctoralFellowships