Colon cancer is the third most common malignancy in men and women and ranks behind only lung cancer in cancer deaths. The most common hereditary disease that predisposes patients to colorectal cancer is Lynch syndrome (LS) which stems from mutations in the mismatch repair (MMR) genes. In addition to its role in LS, flawed MMR has been implicated in 15-40% of sporadic colorectal and other extracolonic tumors indicating a more general role for MMR in tumor protection. Although many functional details of the MMR proteins have emerged, the mechanism by which flawed MMR contributes to tumorigenesis is not fully understood. Faulty MMR results in an elevated mutation rate (mutator phenotype), which has been proposed to lead to an accumulation of oncogene and tumor suppressor mutations that ultimately cause cancer. More recent work has revealed that MMR proteins play an important role in cell cycle arrest and apoptosis in response to certain DNA damaging agents. Thus, MMR mutations may affect tumorigenesis through multiple mechanisms. Our laboratory is interested in understanding what functions of the MMR system are affected during tumorigenesis.

We are addressing this broad question through a multi-pronged approach. First, we are examining  the cellular functions of the MMR proteins and the effects of cancer-causing missense mutations by studying how these mutant proteins perform in DNA repair, cell cycle checkpoint signaling, apoptosis signaling and other functional assays. Most recently, we have begun to characterize the function of the MMR pathway in human pluripotent stem cells and are using CRISPR/Cas9 gene targeting approaches to introduce missense mutations into the endogenous MMR gene loci. Second, we are using pluriopotent stem cells to study the mechanism of the MMR-dependent DNA damage response and how this might impact tumorigenesis. Finally, we are using human colonic organoids to study the effects of MMR mutation on colonic stem cell dynamics and response to damage.

See Dr. Heinen's NBC Connecticut interview on the importance of colon cancer screening on NBC Connecticut at: http://today.uchc.edu/headlines/2010/mar10/coloncancer.html

Not accepting students for Lab Rotations at this time

Lab Rotation Projects
The research in my laboratory involves an array of techniques from cell biology to molecular genetics to genomics to address the fundamental question of why mutations in DNA mismatch repair genes cause cancer. We are predominantly interested in using cancer-associated missense mutations of the MSH2 and MSH6 genes to understand the functions of mismatch repair affected during colorectal tumorigenesis. Projects include:

– Using cell culture models including human pluripotent stem cells to study the functions of mutant MSH2 and MSH6 in damage repair and response.

– Using CRISPR/Cas9 gene engineering to model patient derived missense mutations in the MMR genes in human cells

- Using embryonic stem cells and human colonic organoids to study the effect of MMR mutation on stem cell dynamics

Other projects available and can be discussed depending on student’s interest.

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