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-ß receptor in colon cancer cells with microsatellite instability. Science 268: 1336-1338, 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-\xDF induced suppressor of human gastrointestinal cancers. Proc Natl Acad Sci U S A 101:17468-17473, 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):12098-102, 2006.
Discovery that 15-PGDH regulates tissue stem cells 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’s 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's disease and traumatic brain injury. Proc Natl Acad Sci U S A. 2025;122(21):e2417224122. PMID: 40397680. PMCID: PMC12130856. (*MKS, SDM, AAP 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 (*JR, SDM, DT 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 314:268-74, 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 318:1108-13, 2007.
Jones S, Chen WD, Diehl F, Parmigiani G, Beernwinkel 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 105:4283-4288, 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 hMLH1by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci (USA). 95:8698-8702, 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 26:16-17, 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):736-9, 2012. doi:10.1126/science.1217277. NIHMS: NIHMS488153.
Discovery of methylated DNA biomarkers for early detection of colon cancers and Barrett's esophagus.
Chen W-D, 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: 1124-1132, 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):858-63, 2009. (*SM 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. Science translational medicine. 2018;10(424). doi: 10.1126/scitranslmed.aao5848. PubMed PMID: 29343623; PMCID: PMC5789768.