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Ludwig 2014 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, Jacks, Gertler, Hemann, Hynes, and Lees. Following are structural highlights from the year: • The annual Ludwig Center for Molecular Oncology at MIT Retreat was held at MIT’s Endicott House on June

10, 2014. 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 70 were in attendance.

• Ludwig Center for Molecular Oncology at MIT PIs met regularly 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 three graduate students. • Ludwig Center Postdoctoral Fellowships were awarded to six postdoctoral associates. Most importantly is the research that comes from Ludwig Center Membership as demonstrated in the following Member publications from 2014: Yin H, Xue W, Chen S, Bogorad RL, Benedetti E, Grompe M, Koteliansky V, Sharp PA, Jacks T, Anderson DG. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol, 32:551-553, 2014. PMID24681508; PMC4157757; 10.1038/nbt.2884

Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A, Cai W, Chirino LM, Yang GR, Bronson R, Crowley DG, Sahay G, Schroeder A, Langer R, Anderson DG, Jacks T. Small RNA combination therapy for lung cancer. Proc Natl Acad Sci U S A, 111:E3553-E3561, 2014. PMID25114235; PMC4151750; 10.1073/pnas.1412686111

Pallasch CP, Leskov I, Braun CJ, Vorholt D, Drake A, Soto-Feliciano YM, Bent EH, Schwamb J, Iliopoulou B, Kutsch N, van Rooijen N, Frenzel LP, Wendtner CM, Heukamp L, Kreuzer KA, Hallek M, Chen J, Hemann MT. Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell, 156:590-602, 2014. PMID24485462; PMC3975171; 10.1016/j.cell.2013.12.041

Rohan TE, Xue X, Lin HM, D'Alfonso TM, Ginter PS, Oktay MH, Robinson BD, Ginsberg M, Gertler FB, Glass AG, Sparano JA, Condeelis JS, Jones JG. Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J Natl Cancer Inst, In process, 2014. PMID24895374; PMC4133559; 10.1093/jnci/dju136

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Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, Du J, Kazi JU, Luciano F, Ronnstrand L, Kung AL, Aster JC, Galinsky I, Stone RM, Deangelo DJ, Hemann MT, Stegmaier K. SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia. Cancer Cell, 25:226-242, 2014. PMID24525236; PMC4106711; 10.1016/j.ccr.2014.01.022

Zhao B, Hemann MT, Lauffenburger DA. Intratumor heterogeneity alters most effective drugs in designed combinations. Proc Natl Acad Sci U S A, 111:10773-10778, 2014. PMID25002493; PMC4115561; 10.1073/pnas.1323934111

Naba A, Clauser KR, Lamar JM, Carr SA, Hynes RO. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. Elife, 3:e01308, 2014. PMID24618895; PMC3944437; 10.7554/eLife.01308

Labelle M, Begum S, Hynes RO. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci U S A, 111:E3053-E3061, 2014. PMID25024172; PMC4121772; 10.1073/pnas.1411082111

Naba A, Clauser KR, Whittaker CA, Carr SA, Tanabe KK, Hynes RO. Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver. BMC Cancer, 14:518, 2014. PMID25037231; PMC4223627; 10.1186/1471-2407-14-518

McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, Stewart C, Carter SL, Cibulskis K, Bhutkar A, McKenna A, Dooley A, Vernon A, Sougnez C, Malstrom S, Heimann M, Park J, Chen F, Farago AF, Dayton T, Shefler E, Gabriel S, Getz G, Jacks T. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell, 156:1298-1311, 2014. PMID24630729; PMC4040459; 10.1016/j.cell.2014.02.031

McFadden DG, Vernon A, Santiago PM, Martinez-McFaline R, Bhutkar A, Crowley DM, McMahon M, Sadow PM, Jacks T. p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer. Proc Natl Acad Sci U S A, 111:E1600-E1609, 2014. PMID24711431; PMC4000830; 10.1073/pnas.1404357111

Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, Schinzel AC, Sood S, Rosenbluh J, Kim JW, Zwang Y, Roberts TM, Root DE, Jacks T, Hahn WC. KRAS and YAP1 Converge to Regulate EMT and Tumor Survival. Cell, 158:171-184, 2014. PMID24954536; PMC4110062; 10.1016/j.cell.2014.06.004

Sanchez-Rivera FJ, Papagiannakopoulos T, Romero R, Tammela T, Bauer MR, Bhutkar A, Joshi NS, Subbaraj L, Bronson RT, Xue W, Jacks T. Rapid modelling of cooperating genetic events in cancer through somatic genome editing. Nature, 516:428-431, 2014. PMID25337879; PMC4292871; 10.1038/nature13906

McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol, 16:717-727, 2014. PMID25082194; N/A; 10.1038/ncb3015

Lu H, Clauser KR, Tam WL, Frose J, Ye X, Eaton EN, Reinhardt F, Donnenberg VS, Bhargava R, Carr SA, Weinberg RA. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol, 16:1105-1117, 2014. PMID25266422; PMC4296514; 10.1038/ncb3041

Unternaehrer JJ, Zhao R, Kim K, Cesana M, Powers JT, Ratanasirintrawoot S, Onder T, Shibue T, Weinberg RA, Daley GQ. The Epithelial-Mesenchymal Transition Factor SNAIL Paradoxically Enhances Reprogramming. Stem Cell Reports, 3:691-698, 2014. PMID25316190; PMC4235745; 10.1016/j.stemcr.2014.09.008

Shaul YD, Freinkman E, Comb WC, Cantor JR, Tam WL, Thiru P, Kim D, Kanarek N, Pacold ME, Chen WW, Bierie B, Possemato R, Reinhardt F, Weinberg RA, Yaffe MB, Sabatini DM. Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell, 158:1094-1109, 2014. PMID25171410; PMC4250222; 10.1016/j.cell.2014.07.032

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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 2014 was broken down as indicated in the chart below.

63%7%3%

12%

7%8%

LudwigCenterforMolecularOncologyatMIT

2014Expenditures

FacultyResearch

PilotProjects

AdministrativeSupport

CoreFacilities

GraduateFellowships

PostdoctoralFellowships