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Lecture entitled ‘Unique features of chromosomal unstable cancer’ by prof. Prof. Floris Foijer from University Medical Center Groningen will take place on March 1st, 2022.

Prof. Foijer’s profile.

Abstract of the lecture:

CIN-induced inflammation, a catch-22 for cancer cells?

Chromosomal instability (CIN) leads to aneuploidy and is associated with tumour progression, metastasis, therapy resistance and a poor patient outcome. As CIN and aneuploidy are features that discriminate cancer cells from healthy cells, CIN and/or aneuploidy are considered powerful targets for more selective cancer therapies. However, to develop such therapies, we need to better understand the differences between (cancer) cells that exhibit CIN and cells that do not. We therefore performed an in vivo transposon mutagenesis screen in the hematopoietic system of mice, and compared drivers of resulting hematopoietic malignancies between tumours with and without a CIN phenotype. This screen revealed that specifically the cancers with a CIN phenotype inactivated Stat1 signalling, which coincided with activation of c-Myc. We then engineered cancer cells from untransformed 3T3 cells that recapitulated the drivers identified in our screen and allografted these cells into immuno-proficient mice. We found that Stat1 proficient 3T3 tumours that exhibit CIN are growth impaired and that this coincides with increased immune infiltration compared to 3T3 tumours that do not exhibit CIN. Subsequent inactivation of Stat1 decreased this infiltration and promoted tumour growth. We, therefore, conclude that aneuploid cancers inactivate Stat1 signalling to circumvent immune surveillance. Unexpectedly, we also found that inactivation of stress signalling upstream of Stat1, i.e. cGAS/STING signalling, sensitises cells to CIN. This provides an explanation for why cGAS and STING are rarely inactivated in primary tumours and furthermore exposes a targetable vulnerability of cells that display CIN, which we confirmed in vitro as well as in vivo. Together, these observations suggest that developing cancer cells that exhibit CIN face a catch-22: they need inflammatory signalling for their survival, yet also need to inactivate this to hide from the immune system, which they accomplish by inactivating STAT1 signalling while retaining pro-survival cell intrinsic inflammatory signalling.