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Chromosome Instability and Cancer

Research Summary

Rocio Sotillo studies how chromosome instability arises in tumors and what consequences it has on tumor initiation and maintenance. She also investigates the mechanisms by which chromosome instability facilitates escape from oncogene addiction, leading to tumor recurrence.

Chromosome instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells and is associated with poor prognosis in solid tumors. A subset of these cancers is associated with upregulation of mitotic checkpoint proteins, such as MAD2, HEC1, AURORA A and B, and PPTG. These checkpoint proteins are part of a surveillance mechanism that prevents aneuploidy by delaying sister chromatid separation until all chromosomes are properly attached to the mitotic spindle and aligned at the metaphase plate. We study the consequences of overexpression of distinct mitotic checkpoint proteins in normal and neoplastic growth using genetically engineered mouse models.

Whether aneuploidy is a cause or a consequence of cancer has until recently been a matter of significant debate. We showed that mice that overexpress Mad2 (an integral component of the mitotic checkpoint) develop chromosomal instability and aneuploidy. More importantly, high Mad2 levels also result in the formation of aggressive tumors in multiple organs, implying that the generation of aneuploidy is sufficient to form tumors in vivo. In addition, overexpression of Hec1 (Highly Expressed in Cancer 1), a core component of the outer kinetochore, the protein complex that serves as a scaffold between microtubules and centromeric DNA, results in spindle checkpoint overactivation and aneuploidy that is also sufficient to generate tumors in vivo. Together, these data suggest that CIN can initiate tumors in a variety of tissues and should be considered a risk factor in modern preventive care.

Growing evidence suggests that CIN plays a major part in the pathogenesis of lung cancer. Human lung cancer cells have been shown to carry frequent structural chromosomal abnormalities such as deletions of specific regions or numerical changes in their chromosome numbers. However, current mouse models of lung cancer show stable genomes. Therefore, to better recapitulate human disease, we combined Mad2 overexpression with a mutant Kras oncogene, a gene frequently mutated in human lung cancer. Our studies show that the CIN generated by high levels of Mad2 cooperates with Kras to produce more aggressive and unstable lung tumors.

Several in vitro and in vivo studies have established that inhibition of an initiating oncogene often leads to extensive tumor cell death and profound tumor regression. This phenomenon, known as oncogene dependence, has led to the hypothesis that the development of targeted therapies against oncogenes known to be associated with human cancers should be an effective anticancer strategy. Unfortunately, the clinical implementation of the first generation of these agents (imatinib targeting the BCR-ABL kinase, trastuzumab targeting ERBB2, and gefitinib and erlotinib targeting the EGF receptor), though initially positive, has consistently resulted in tumor relapse and the development of more aggressive cancers that no longer respond to the original treatment.

Because many tumors acquire genomic instability early in their development, we tested the effects of CIN combined with oncogene dependence. We have recently shown that the frequency of tumor recurrence following oncogene withdrawal is markedly increased in the context of chromosomal instability, demonstrating that even successful targeted therapy of a known driving oncogene might fail in the clinic as a result of instability in the primary tumor. This finding adds significant complexity to modern approaches to cancer therapy.

My current efforts are aimed at identifying the molecular mechanisms that lead to CIN and the consequences it has in tumor initiation and progression. We are also interested in understanding the mechanism of how CIN promotes tumor relapse. We propose that CIN might produce more genetic diversity within the cancer cell population or enhance the rate of mutations. Either could allow a subset of these cancer cells to acquire additional oncogenic mutations or lose tumor suppressor genes, which are no longer dependent on the initial oncogenic pathway for survival. It is possible that CIN in the primary tumor accelerates the disruption of DNA repair pathways, thereby facilitating the generation of point mutations.

We are currently investigating these different mechanisms by generating transgenic mouse models that combine CIN with several inducible oncogenes that can be targeted therapeutically. Our previous studies underscored the importance of generating mouse models that faithfully recapitulate the biology of human disease. Mouse models of cancer, which often show benign levels of CIN relative to human cancers, may overestimate the efficacy of clinical drug candidates. These preclinical models are necessary to provide a valuable system to test combined targeted and classical chemotherapeutical approaches for their efficacy in the context of tumor initiation, maintenance, and relapse.

In parallel to our in vivo studies, and in collaboration with Martin Jechlinger (European Molecular Biology Laboratory), we are establishing the conditions to grow primary lung epithelial cells in a three-dimensional in vitro culture system. These three-dimensional cultures will allow us to extensively characterize the properties and fates of surviving cells following oncogene withdrawal in the presence or absence of CIN.

Grants from the European Research Council, Marie Curie Action, and the Italian Association for Cancer Research provided partial support for these projects.

As of January 17, 2012

Scientist Profile

International Early Career Scientist
European Molecular Biology Laboratory (Monterotondo, Italy)
Cancer Biology, Molecular Biology