Albert Einstein Cancer Center

Selected Achievements: Biology of Colon Cancer

The Edelmann laboratory made endonuclease-deficient Pms2E702K knock-in mice which displayed increased genomic mutation rates and a strong cancer predisposition establishing that the DNA mismatch repair protein PMS2 has endonuclease activity with distinct biological functions and is essential for genome maintenance and tumor suppression. (Proc Natl Acad Sci U S A. 107:13384-9, 2010. PMID: 20624957) 

 

The Cuervo laboratory identified consistent up-regulation of chaperone mediated autophagy and an increase in CMA components in tumor cells suggesting that targeting this autophagic pathway may have broad antitumorigenic potential. (Sci Transl Med. 3:109ra117, 2011. PMID: 22089453) 

 

Lin and collaborators developed a novel mouse model of IBD-colorectal cancer progression by specifically targeting Stat3 inactivation to macrophages. This disrupted immune regulation, mTOR-Stat3 signaling, and epithelial hyperproliferation were linked to the development of tumors at sites of inflammation. (Am J Pathol 176:952-967, 2010. PMID 20042677) 

 

Augenlicht and colleagues reported that (i) there is an elevation of Wnt signaling, shift to glycolytic metabolism and altered lineage allocation of epithelial cells in the histologically normal colonic mucosa of mice at nutritional risk for common sporadic colon cancer well before tumors form (Cancer Res. 68:7803, 2008. PMID: 18829535 -featured on cover and highlights section) and (ii) that Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer.  (Proc Natl Acad Sci U S A. 108:10272, 2011. PMID: 21652773) 

 

Utilizing massively-parallel sequencing of single cell genomes, the Vijg laboratory identified (i) significant intra-tissue mutational heterogeneity as somatic cells age and (ii) the fraction of cells with mutations that can result in malignant transformation. (Nucleic Acids Res. 40:2032-204, 2012. PMID: 22086961; Mutat Res. 729:1-15, 2012 PMID: 22016070) 

 

Using a novel technology of in situ transcription site imaging in single cells, Singer and Augenlicht identified specific transcription site activation markers of chemotherapeutic sensitivity and resistance of colon cancer cells. (Cancer Res. 68:4977, 2008. PMID: 18593893) and discovered the haploinsufficiency of Apc in supporting normal patterns and regulation of cell maturation along the crypt-luminal axis of the intestinal mucosa (Cancer Res, 70: 5348, 2010. PMID 20570902). 

 

Pamela Stanley and collaborators reported that mucus hypersecretion upon inhibition of Notch signaling is accompanied by alteration of the mucus-associated flora likely contributing to the development of enterocolitis and revealing an important potential complication in strategies to target Notch signaling in therapeutic approaches to colon cancer. (Gastroenterology.135:849, 2008. PMID: 18621050) 

 

The Guha laboratory reported that Rspo1 is mitogenic for intestinal stem cells and protects normal mucosal cells, but not tumor cells, from abdominal radiation-induced gastrointestinal toxicity suggesting that this growth factor may improve the therapeutic ratio of abdominal irradiation for GI malignancies. (PLoS One. 4:e8014, 2009. PMID: 19956666). 

 

The Mani laboratory showed that activation of PXR increased chemoresistance in tumor cells and augmented the growth, invasion, and metastasis of both human colon tumor cell lines and xenografts, observations relevant to the design of therapeutic regimens for colon carcinoma. (J. Clin Invest. 121:3220-32, 2011. PMID: 21747170) 

 

Mani, Redinbo (UNC) and collaborators reported that blocking bacterial beta glucuronidase in vivo alleviated the significant diarrhea that is a major cause of the dose limiting toxicity of CPT-11.  (Science 30:6005, 2010.  PMID: 21051639 

 

Mariadason, Goel and collaborators reported that PIK3CA mutation/PTEN expression status predicts lack of response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab, leading directly to a completed clinical validation evaluating the expression of PTEN and mutations in KRAS, BRAF, PIK3CA, PIK3R1, AKT1, and PTEN genes as predictors of response to anti-EGFR therapy for metastatic colon cancer. (Cancer Res.  68:1953, 2008; Clin Colorectal Cancer 11:143, 2012) 

 

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