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Sotillo ERC Investigator

Mitotic chromosomal instability and oncogene dependence

sotillo_s

Figure 2. A) The mitotic checkpoint complex (Mad2, Cdc20, BubR1 and Bub3) is shown to inhibit the anaphase promoting complex/cyclosome (APC/C) until the last kinetochore is correctly attached to microtubules. B) Evidence of lagging chromosomes and aneuploidy measured by FISH analysis on cells overexpressing Mad2. C) MR images of Kras transgenic mice (TI-K) and Kras+Mad2 (TI-KM) mice on doxycycline at indicated times showing lung tumors (yellow circles) (left panel), after 2-6 weeks of doxycycline withdrawal showing complete regression (middle panel) and after 14-16 weeks off doxycycline (right panel) showing recurrent tumors in mice that overexpress Mad2. Moreover recurrent tumors from these mice are highly aneuploid.

Previous and current research

Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells. Overexpression of the mitotic checkpoint protein Mad2, commonly found in human tumors, leads to CIN and the development of aneuploid tumors in mouse models. Moreover, CIN can facilitate escape from oncogene addiction (the dependence of tumor cells on their initiating lesion for survival) and may be responsible for tumor relapse after targeted therapies. Very little is known about the mechanism of how and when CIN promotes tumor relapse.

Our lab will focus on understanding the molecular mechanisms that lead to CIN and the consequences it may have in tumor initiation, suppression and relapse, hoping that the genes or proteins identified could be targeted therapeutically. We will use a combination of mouse genetics and highly innovative three-dimensional in vitro culture systems.

Future projects and goals

  • To study the dependence of tumor cells on the mitotic checkpoint in vivo and evaluate the potential for therapeutic interference with mitotic checkpoint genes.
  • To study the effects of tumor regression and recurrence in chromosomally unstable tissues.
  • To analyse the dual role of chromosome instability (tumor initiating and tumor suppressive) dependent on levels of aneuploidy, tissue type and molecular nature of the cooperating lesion(s).