Posted October 11, 2018
Samuel Bakhoum, M.D., Ph.D., Memorial Sloan Kettering Cancer Center

Chromosomal instability (CIN) results in an abnormal number or structure of chromosomes within a cell and has been associated with an increased risk of recurrence and death in a variety of cancers, including breast, prostate, colorectal, and non-small cell lung cancers. While CIN is a hallmark of cancer that has been shown to correlate with metastasis, the mechanistic role of CIN in metastatic progression remains to be elucidated.

With support from a Fiscal Year 2015 Breast Cancer Research Program Breakthrough Award - Funding Level 1 - Partnering PI Option, Dr. Bakhoum and his research team sought to determine the mechanisms by which CIN contributes to metastasis in triple-negative breast cancer (TNBC). As described in a recent paper published in Nature, the research team over-expressed (CIN-low) or under-expressed (CIN-high) proteins responsible for maintaining chromosome integrity during cell division in TNBC cell lines and showed that errors in chromosome segregation (CIN-high) activate the noncanonical NF-?B (nuclear factor kappa-light-chain-enhancer of activated B-cells) pathway in a cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes)-dependent manner. Activation of noncanonical NF-?B via cGAS-STING signaling in CIN-high TNBC cells caused the cancer cells to transition to a mesenchymal state, indicative of metastatic potential, increase their invasive capabilities, and activate inflammatory pathways which promoted metastasis.

Using a mouse model of TNBC, Dr. Bakhoum and colleagues confirmed that mice injected with CIN-low TNBC cells significantly lowered the cancer cells ability to colonize in the bone, lungs, and brain thus decreasing the overall metastatic burden. Overall survival was also significantly improved in mice harboring CIN-low metastatic breast tumors when compared to CIN-high metastases (207 days compared to 70 days, respectively). Moreover, the researchers identified a 23-gene CIN signature that predicted distant metastasis-free survival in a meta-analysis and validation cohort of patients with breast cancer, independent of tumor subtype, grade, or lymph node status.

Data from Dr. Bakhoum and his research team provide a mechanistic connection between CIN and the evolution of metastasis in TNBC. These data suggest that CIN results in a shift to a chromosomally unstable state associated with an upregulation of inflammatory pathways and increased metastatic potential. In addition, the CIN signature identified by this research team could serve as a prognostic tool for clinicians, as well as offer the possibility for the development of future therapeutic targets aimed at reducing CIN.

Dr. Samuel Bakhoum (center) and his team

References:

Bakhoum SF, Ngo B, Laughney AM, et al. 2017. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553(7689):467-472.

Link:

Public and Technical Abstracts: Examining the Role of Chromosomal Instability in Breast Cancer Evolution

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