Cancer Dynamics

Members

Arijit Chakravarty, Ph.D.

Cordelia Ziraldo, Ph.D. candidate, Joint CMU-Pitt Ph.D. Program in Computational Biology

Overview

We are interested in applying a systems biology perspective to the study of the causes and consequences of chromosomal instability (CIN) in cancer.

CIN is a hallmark of cancer – 85% of all cancers show an increased rate of loss or gain of chromosomes – and is thought to occur early and play a driving role in cancer progression. Paradoxically, while many oncogenes and carcinogens have been shown to cause CIN, many cancer treatments (such as ionizing radiation, antimitotics and DNA damaging agents) have also been demonstrated to cause CIN.

One potential explanation for this paradox is that an optimal level of chromosomal instability provides a fitness advantage for the tumor population, while CIN levels above this optimum cause a catastrophic loss of fitness. This is analogous to the error catastrophe hypothesis in RNA viral evolution, and provides a mechanistic basis for the therapeutic window for traditional chemotherapeutics.

Specifically, we are interested in developing mathematical models of CIN in cancer progression, and extending these to model the action of chemotherapeutics. The goal is to use these models to generate hypotheses and then verify model-generated predictions in vivo.

We are also interested in the physical mechanism by which chemotherapeutic agents cause chromosomal instability. One direct mechanistic explanation for this phenomenon is that DNA damage leads to defective assembly of the mitotic spindle. As spindle assembly is a dynamic process, requiring force contributions from motor proteins, structural proteins and chromosomes, chromosomal damage would be expected to cause imbalances in the forces acting on the mitotic spindle during assembly. We are interested in building mathematical models of force balance in the mitotic spindle, in the presence and absence of chromosomal damage. Such models would then be used to generate unobvious biological hypotheses that can then be tested at the bench.