Thursday, June 18, 2009

Developing a Genomic Signature for Epirthelial Mesenchymal Tranrsition

KH presents on Developing a Genomic Signature for Epithelial Mesenchymal Transition (EMT)

Background in the Potti lab. NEJM 2006; 355:570.
Gene expression patterns were examined in a Cohort of Duke patients with early stage NSCLC, then validated in two independent cohorts (CALGB, ACOSOG). 133 genes in the developed signature (k-ras, MDR upregulation, and down regulation of tumor suppression). Strong predictions of recurrence and survival.

Currently the lab is working wuth a 52 gene signature for radiation sensitivity which was developed initially at the University of Chicago. Resistant clones were selected from a cell line that was serially irradiated and the gene signature differentiates between the resistant selected clones and the initial sensitive cell line. The Potti lab has confirmed this in previously unirradiated cell lines, and has predictive value in predicting radiation response in vitro.

This signature is then clinically tested in samples from patients with head and neck cancer and in group with rectal cancer. Accuracy for response to RT was on the order of 75% for association with pCR in the rectal cancer patients, and (?radiographic) response in the Head and Neck patients.

A current direction is integrating mircoRNAs into the gene chips, which requires no additional technology, just different probes.

Switching gears to EMT.

Epithelial Mesenchymal Transition (EMT) occurs in normal embyogenesis. It is also implicated in Lung and Kidney fibrosis, and possibly radiation resistance. Perhaps most intriguingly, EMT is also implicated in the invasion and metastasis process of carcinomas (and an MET [mesenchymal to epithelial tranisition] process then occurs after establishement of a distant colony).

E Cadherin and multiple other pathways (including the Hedgehog pathway) regulate this process. Coculturing with myofibroblasts release Hh(hedgehog) into the microenvironment, and this has been shown to produce EMT in cholangiocytes.

Plan will be two develop an EMT model in NSCLC lines via either coculturing with myofibroblasts or transfection with adenovirus vectors carrying Hh DNA, then developing a gene signature for this process.

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