Extracellular control of chromosomal instability and maintenance of intra-tumoral heterogeneity

Aim: Current cancer treatments are challenged by the plasticity of cancer cells, largely influenced by chromosomal instability (CIN) leading to variations in karyotype known as tumor-specific aneuploidy, which in turn, leads to intratumor cellular heterogeneity (TH). Cells with certain chromosomal defects often survive treatment and the growthassociated states of TH persist in recurrent tumors. Modulation of the CIN rate seems to reside within the tumor itself. In an attempt to develop a therapy targeting cancer plasticity, we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas. Methods: Chr7-fluorescence in situ hybridization was applied on various grades of gliomas, in vitro cultures and intracranial xenografts of two syngeneic glioma lines (U251 and U251-NS) derived from various cell-inoculating densities, with or without EFEMP1 overexpression. Results: A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas. A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression. Conclusion: Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells, and EFEMP1 is one of these factors.