Using quantitative imaging microscopy to explore and target the molecular origins of cancer

The identification of novel drug targets and the development of next generation therapeutic strategies remain elusive goals for cancer researchers. We believe that the aberrant molecular events driving cancer development and progression can be exploited to devise novel therapeutic strategies that are highly selective towards cancer cells. Chromosome instability (CIN) is a form of genome instability that induces ongoing changes in chromosome complements and thus, is a driver of cell-to-cell heterogeneity. CIN is prevalent in many cancer types and is associated with cellular transformation, intratumoral heterogeneity, metastasis, the acquisition of drug resistance and poor patient prognosis. Despite all these associations, the aberrant genes, proteins and cellular processes (i.e. molecular determinants) giving rise to CIN remain largely unknown. To expand our basic understanding of the molecular determinants of CIN and cancer mandated the use of single-cell approaches capable of quantifying the cell-to-cell heterogeneity induced by CIN. Accordingly, we created several quantitative imaging microscopy approaches and employed them to evaluate hundreds of candidate CIN genes. Here, we present these approaches and their application in the discovery and characterization of a subset of CIN genes with pathogenic implications for cancer. We subsequently discuss the use of additional quantitative approaches to identify novel drug targets that selectively target and kill cancer cells harboring defects in CIN genes. Collectively, our work provides novel insight into the pathogenic origins of cancer that is crucial to develop the next generation of drug targets aimed at better combating the disease.

Learning Objectives:

1. Define chromosome instability (CIN) and describe its relationship with cancer.

2. Detail three quantitative imaging microscopy approaches used to identify CIN genes.

3. Describe how quantitative imaging microscopy approaches can be used to identify novel drug targets.