Markowitz Lab Research
Key discoveries and areas of study
Discovery of TGF-beta receptors as colon cancer tumor suppressor genes
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RW, Zborowska E, Kinzler KW, Vogelstein B, Brattain M, Willson JKV. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 268:1336 to 1338, 1995.
Discovery of the 15-PGDH pathway as a colon cancer tumor suppressor pathway and as an effector of TGF-beta mediated tumor suppression
15-PGDH has a unique mechanism of action. By catalyzing the enzymatic inactivation of prostaglandins, 15-PGDH acts as a metabolic antagonist of the COX-2 oncogene.
Yan M, Rerko R, Platzer P, Dawson D, Willis J, Tong M, Lawrence E, Lutterbaugh J, Lu S, Willson J, Luo G, Hensold J, Tai H, Wilson K, Markowitz S. 15-Hydroxyprostaglandin Dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta induced suppressor of human gastrointestinal cancers. Proc Natl Acad Sci U S A. 101:17468 to 17473, 2004. Chosen as a From the Cover Article by PNAS and profiled in Research Highlights in Nature Reviews Cancer 5(1):5, 2005.
Myung SJ, Rerko RM, Yan M, Platzer P, Guda K, Dotson A, Lawrence E, Dannenberg AJ, Lovgren AK, Luo G, Pretlow TP, Newman RA, Willis J, Dawson D, Markowitz SD. 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis. Proc Natl Acad Sci U S A. 103(32):12098 to 12102, 2006.
Discovery that 15-PGDH regulates tissue stem cell response to injury and the discovery of the first in vivo active small molecule 15-PGDH inhibitor as a drug for potentiating tissue regeneration in the bone marrow, colon, and other organs
Zhang Y, Desai A, Yang SY, Bae KB, Antczak MI, Fink SP, Tiwari S, Willis JE, Williams NS, Dawson DM, Wald D, Chen WD, Wang Z, Kasturi L, Larusch GA, He L, Cominelli F, Di Martino L, Djuric Z, Milne GL, Chance M, Sanabria J, Dealwis C, Mikkola D, Naidoo J, Wei S, Tai HH, Gerson SL, Ready JM, Posner B, Willson JK, Markowitz SD. Inhibition of the prostaglandin degrading enzyme 15-PGDH potentiates tissue regeneration. Science. 2015;348(6240):aaa2340. doi:10.1126/science.aaa2340. PubMed PMID: 26068857. PMCID: 4481126.
Discovery that 15-PGDH regulates inflammatory cells and that 15-PGDH inhibition blocks neurodegeneration in Alzheimer disease models
Koh Y, Vazquez-Rosa E, Gao F, Li H, Chakraborty S, Tripathi SJ, Barker S, Bud Z, Bangalore A, Kandjoze UP, Leon-Alvarado RA, Sridharan PS, Cordova BA, Yu Y, Hyung J, Fang H, Singh S, Katabathula R, LaFramboise T, Kasturi L, Lutterbaugh J, Beard L, Cordova E, Cintron-Perez CJ, Franke K, Fragoso MF, Miller E, Indrakumar V, Noel KL, Dhar M, Ajroud K, Zamudio C, Lopes F, Bambakidis E, Zhu X, Wilson B, Flanagan ME, Gefen T, Fujioka H, Fink SP, Desai AB, Dawson D, Williams NS, Kim YK, Ready JM, Paul BD, Shin MK, Markowitz SD, Pieper AA. Inhibiting 15-PGDH blocks blood-brain barrier deterioration and protects mice from Alzheimer disease and traumatic brain injury. Proc Natl Acad Sci U S A. 2025;122(21):e2417224122. PMID: 40397680. PMCID: PMC12130856. Markowitz, Pieper, and Shin co-corresponding authors. Highlighted as subject of a co-published PNAS Commentary.
Discovery of the molecular mechanism by which 15-PGDH inhibitors recognize and subvert a hidden pocket crucial to the normal function of the 15-PGDH enzyme
Huang W, Li H, Kiselar J, Fink SP, Regmi S, Day A, Yuan Y, Chance M, Ready JM, Markowitz SD, Taylor DJ. Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system. Nat Commun. 2023;14(1):784. PMID: 36774348. PMCID: PMC9922282. Ready, Markowitz, and Taylor co-corresponding authors.
Sequencing of the colon cancer genome and the analysis of the genomes of metastatic colon cancers
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science. 314:268 to 274, 2006.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B. The Genomic Landscapes of Human Breast and Colorectal Cancers. Science. 318:1108 to 1113, 2007.
Jones S, Chen WD, Diehl F, Parmigiani G, Beerenwinkel N, Antal T, Traulsen A, Nowark M, Siegel C, Velculescu V, Kinzler K, Vogelstein B, Willis J, Markowitz SD. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A. 105:4283 to 4288, 2008. PMCID: PMC2393770.
Discovery of key epigenetic events in GI carcinogenesis
Veigl ML, Kasturi L, Olechnowicz J, Ma A, Lutterbaugh JD, Periyasamy S, Li G-M, Drummond J, Modrich PL, Sedwick WD, Markowitz SD. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A. 95:8698 to 8702, 1998.
Grady W, Willis J, Guilford P, Dunbier A, Toro T, Lynch H, Wiesner G, Ferguson K, Eng C, Park JG, Kim SJ, Markowitz S. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nature Genet. 26:16 to 17, 2000.
Akhtar-Zaidi B, Cowper-Sal-Iari R, Corradin O, Saiakhove A, Bartels C, Balasubramanian D, Myeroff L, Lutterbaugh J, Jarrar A, Kalady M, Willis J, Moore J, Tesar P, LaFramboise T, Markowitz SD, Lupien M, Scacheri P. Epigenomic enhancer profiling defines a signature of colon cancer. Science. 336(6082):736 to 739, 2012. doi:10.1126/science.1217277. NIHMS: NIHMS488153.
Discovery of methylated DNA biomarkers for early detection of colon cancers and Barrett's esophagus
Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, Myeroff L, Platzer P, Lu S, Dawson D, Willis J, Pretlow TP, Lutterbaugh J, Katuri L, Willson JKV, Rao JS, Shuber A, Markowitz SD. Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst. 97:1124 to 1132, 2005.
Li M, Chen WD, Papadopoulos N, Goodman SN, Bjerregaard NC, Laurberg S, Levin B, Juhl H, Arber N, Moinova H, Durkee K, Schmidt K, He Y, Diehl F, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW, Markowitz SD, Vogelstein B. Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol. 27(9):858 to 863, 2009. Markowitz SD corresponding author. PMCID: PMC2847606.
Moinova HR, LaFramboise T, Lutterbaugh JD, Chandar AK, Dumot J, Faulx A, Brock W, De la Cruz Cabrera O, Guda K, Barnholtz-Sloan JS, Iyer PG, Canto MI, Wang JS, Shaheen NJ, Thota PN, Willis JE, Chak A, Markowitz SD. Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett's esophagus. Sci Transl Med. 2018;10(424). doi:10.1126/scitranslmed.aao5848. PubMed PMID: 29343623. PMCID: PMC5789768.