Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo

Abstract

Chromosomal instability is a hallmark of cancer, but also an instigator of aneuploidy-induced stress, reducing cellular fitness. To better understand how cells with CIN adjust to aneuploidy and adopt a malignant fate in vivo, we performed a genome-wide mutagenesis screen in mice. We find that specifically aneuploid tumors inactivate Stat1 signaling in combination with increased Myc activity. By contrast, loss of p53 is common, but not enriched in CIN tumors. Validation in another tissue type confirmed that CIN promotes immune cell infiltration, which is alleviated by Stat1 loss combined with Myc activation, but not with p53 inactivation, or Myc activation alone. Importantly, we find that this mechanism is preserved in human aneuploid cancers. We conclude that aneuploid cancers inactivate Stat1 signaling to circumvent immune surveillance.

Chromosomal instability and inflammation: a catch-22 for cancer cells

“…Mechanistically, Hong et al found that activation of STAT1 signaling promotes cell death in breast cancer cells with induced CIN, suggesting a tumor suppressive role for STAT1 signaling in cancers with CIN (Hong et al 2022). In alignment with this tumor suppressive role of STAT1, an in vivo genome-wide transposon mutagenesis screen revealed that specifically tumors that display CIN inactivate inflammatory signaling through STAT1 inactivation in combination with increased c-Myc activity compared to euploid tumors (Schubert et al 2021). Here, STAT1 signaling in cancer cells with CIN was associated with immune cell attraction and activation, which was decreased upon loss of STAT1.…”

“…In senescent cells with complex aneuploid karyotypes, NF-κB signaling contributes to natural killer cell-mediated elimination. However, natural killer cell-mediated elimination was not induced in aneuploid cancer cell lines, despite upregulation of NF-κB signaling, suggesting that aneuploid cancer cells circumvent immune activation et al 2017; Schubert et al 2021;Wang et al 2021). While these studies reveal clear interactions between CIN phenotypes and NF-κB signaling, the type of interaction is likely context-specific.…”

“…In the context of cancer, including tumors with CIN, STAT1 has generally been shown to exert tumor suppressor properties (Avalle et al 2012). A decrease or loss of STAT1 activity has been reported for many cancer types (Meissl et al 2017), including tumors with CIN (Schubert et al 2021), and high STAT1 expression levels correlate with better clinical outcomes (Chen et al 2013;Gordziel et al 2013). Mechanistically, tumor cell-intrinsic STAT1-mediated tumor suppression is due to its antiproliferative effects via cell cycle inhibition and induction of cell death (Bromberg 2001;Meissl et al 2017).…”

“…Cell-intrinsic inflammatory signaling was initially reported to increase the immunogenicity of tumors with CIN via cGAS/STING-mediated activation of the type I IFN response followed by STAT1 signaling, thereby driving immune infiltration (Tripathi et al 2019;Schubert et al 2021). Therefore, efforts were made to activate this signaling using, for instance, STING agonists in clinical trials, though not (yet) specifically for CIN + cancers (Le Naour et al 2020).…”

“…This tumor cell-intrinsic inflammatory signaling was reported to increase the immunogenicity of tumors with CIN, thereby enhancing immune cell recruitment, early tumor detection, and tumor cell clearance (Santaguida et al 2017;Wang et al 2021). However, other studies point toward a more complicated relationship between CIN and immune surveillance, as CIN has been associated with immune evasion rather than immune surveillance in the context of tumorigenesis (Davoli et al 2017;Schubert et al 2021;Li et al 2021). This suggests that tumors with CIN have evolved more complex mechanisms to adjust or use CIN-induced inflammation in a pro-tumorigenic manner.…”