Radiation and Cancer Biology

SS 33 - Biology 6 - Radiation Biology and Radiation Sensitizers

242 - Chromosomal Instability Drives Metastasis Through a Cytosolic DNA Response

Wednesday, October 24
8:25 AM - 8:35 AM
Location: Room 004

Chromosomal Instability Drives Metastasis Through a Cytosolic DNA Response
S. Bakhoum1, B. Ngo2, A. Bakhoum1, J. A. Cavallo-Fleming1, C. W. Murphy2, S. N. Powell1, and L. Cantley2; 1Memorial Sloan Kettering Cancer Center, New York, NY, 2Weill Cornell Medicine, New York, NY

Purpose/Objective(s): Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. It is also a conspicuous consequence of ionizing radiation. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. In a therapeutic context, chromosome segregation errors can mediate cell death and mitotic catastrophe after radiation treatment, however the consequences of persistent chromosomal instability in cells that persist after therapy remains poorly understood.

Materials/Methods: Here we analyze primary tumors matched pairs for evidence of chromosomal instability using three orthogonal experimental approaches. We also make use of genetic models of chromosomal instability to selectively alter chromosome segregation rates in otherwise isogenic models to dissect the role of mitotic chromosome missegregation on tumor evolution.

Results: We show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous as well as a cell extrinsic response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Interestingly, tumor cells completely blunt canonical interferon production downstream of cytosolic DNA. Interestingly however, activation of cGAS promotes an immune microenvironment that facilitates the progression of metastasis. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner.

Conclusion: By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Author Disclosure: S. Bakhoum: Employee; Memorial Sloan Kettering Cancer Center. Member of the public affairs committee; American Society for Cell Biology. B. Ngo: None. A. Bakhoum: None. J. Cavallo-Fleming: None. C.W. Murphy: None.

Samuel Bakhoum, MD, PhD

Memorial Sloan Kettering Cancer Center

Disclosure:
Employment
Memorial Sloan Kettering Cancer Center: Clinical fellow: Employee, Research Fellow: Employee

Leadership
American Society for Cell Biology: Member of the public affairs committee

Presentation(s):

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