Chromosomal instability as an architect of the cancer stemness landscape

Abstract

Despite a critical role for tumor-initiating cancer stem cells (CSCs) in breast cancer progression, major questions remain about the properties and signaling pathways essential for their function. Recent discoveries highlighting mechanisms of CSC-resistance to the stress caused by chromosomal instability (CIN) may provide valuable new insight into the underlying forces driving stemness properties. While stress tolerance is a well-known attribute of CSCs, CIN-induced stress is distinctive since levels appear to increase during tumor initiation and metastasis. These dynamic changes in CIN levels may serve as a barrier constraining the effects of non-CSCs and shaping the stemness landscape during the early stages of disease progression. In contrast to most other stresses, CIN can also paradoxically activate pro-tumorigenic antiviral signaling. Though seemingly contradictory, this may indicate that mechanisms of CIN tolerance and pro-tumorigenic inflammatory signaling closely collaborate to define the CSC state. Together, these unique features may form the basis for a critical relationship between CIN and stemness properties.

Keywords: breast cancer; cancer stem cell; chromosomal instability; inflammation; metastasis; stress tolerance.

FIGURE 1

The dual effects of chromosomal instability (CIN) on cancer cells. CIN can paradoxically act as a lethal stress limiting the ability of tumor cells to transform or progress (top), or initiate pro-metastatic antiviral signaling that enhances cell survival and proliferation (bottom).

FIGURE 2

Signaling pathways mediating the CSC response to CIN. CSC resistance to the stress caused by CIN occurs through preventing DNA damage or inactivating STAT1-mediated cell death (left panel), while STING-induced cytokines such as IL-6 drive cell survival and proliferation via STAT3 activation (right panel). ECM, extracellular matrix; dsDNA, double-stranded DNA; ER, endoplasmic reticulum.