Intra-Tumor Heterogeneity

A Molecular Understanding of Signaling Heterogeneity in Non-Small Cell Lung Cancer

While there are many molecular and signaling differences between lung cancers from different patients (“inter-tumor heterogeneity”) there has been little understanding of heterogeneity that develops within individual tumors.

In collaboration with the laboratory of Drs. Steven Altschuler and Lani Wu (formerly at UT Southwestern, now at University of California, San Francisco) we have been studying heterogeneity of signaling pathways within individual lung cancers. To do this we have used a unique model system of immortalized normal lung epithelial cells into which we have introduced defined oncogenetic changes such as mutant KRAS, p53, C-myc, LKB1, BCL2.

This model system is easy to perturb and is useful to study heterogeneity of a few pathways in isolation. We established methods to quantify signaling heterogeneity from immunofluorescence images acquired by a high-throughput, high-content image acquisition platform. We are investigating the nature of this heterogeneity in terms of defined signaling states, its genetic causality and its response to microenvironment. We are then applying our methods to a diverse panel of NSCLC lines and classifying them according to their signaling heterogeneity.

Our study provides a molecular understanding of onco-gene induced signaling pathway alterations in single cells and this has important implications for how lung cancers will respond to targeted and chemotherapy.