Markowitz Colon Cancer Laboratory

Our mission is to identify key genetic causes of colon cancer and to develop better ways for prevention, early detection, and treatment of this disease.

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Key areas in which we have contributed and study are:

1.    The discovery of TGF-beta receptors as colon cancer tumor suppressor genes.

2.    The 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.

3.     The discovery that differences in colon 15-PGDH provides the molecular basis for individual sensitivity or resistance to the cancer preventive effects of aspirin.

4.     The 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.

5.    The sequencing of the colon cancer genome, and the analysis of the genomes of metastatic colon cancers.

6.    The discovery of key epigenetic events in GI carcinogenesis.

7.    The discovery of methylated DNA biomarkers for early detection of colon cancers and Barrett’s esophagus. 



Key publications from these studies include:

1.    The 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.   

2.    The 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-ß 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. 

4.     The 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.

3.     The discovery that differences in colon 15-PGDH provides the molecular basis for individual sensitivity or resistance to the cancer preventive effects of aspirin.

Yan M, Myung SJ, Fink SP, Lawrence E, Lutterbaugh J, Yang P, Zhou X, Liu D, Rerko RM, Willis J, Dawson D, Tai HH, Barnholtz-Sloan JS, Newman RA, Bertagnolli MM, Markowitz SD. 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. Proc Natl Acad Sci U S A 106(23):9409-13, 2009. PMCID: PMC2695050

Fink SP, Yamauchi M, Nishihara R, Jung S, Kuchiba A, Wu K, Cho E, Giovannucci E, Fuchs CS*, Ogino S*, Markowitz SD*, Chan AT*. Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of 15-Hydroxyprostaglandin Dehydrogenase (HPGD). Science translational medicine. 2014;6(233):233re2. PMCID: PMC4030641. (*SDM, ATC, CSF, SO equal contributions) (First author SPF from Markowitz lab.)

5.    The 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

6.    The 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 (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.

6.    The 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-specifc 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, Leidner RS, Ravi L, Lutterbaugh J, Barnholtz-Sloan JS, Chen Y, Chak A, Markowitz SD*, Willis JE.  Aberrant vimentin methylation is characteristic of upper gastrointestinal pathologies. Cancer Epidemiol Biomarkers Prev.  Apr;21(4):594-600, 2012.  (Journal Cover Article) (*SM corresponding author). PMCID: PMC3454489.

7.    Sandy’s authored reviews and editorials on colon cancer include:

Markowitz, SD, and Bertagnolli, MM. Molecular basis of colorectal cancer. N Engl J Med 2009;361:2449-2460.

Markowitz SD. Aspirin and colon cancer--targeting prevention? N Engl J Med 2007;356(21):2195-8.