Surprise — it wasn’t: RNA-seq and histology show that moderate/high CIN causes massive cell death, triggering regeneration without immune infiltration — providing the non–cell-autonomous push that fuels tumorigenesis. (5/5)

One possibility of such a mechanism: CIN may mimic TPA in promoting tumorigenesis. Indeed, moderate/high CIN could partially replace TPA in the DMBA/TPA regimen.
But what TPA effect was CIN mimicking? Inflammation? (4/5)

Now the twist: despite being induced under moderate/high CIN, these tumors are made of low CIN cells across other tumor types.

So what’s happening?

Moderate/high CIN drives the outgrowth of rare low-CIN tumor cells through a non–cell-autonomous mechanism which doesn't happen in only low CIN. (3/5)

CIN levels matter!

We used CiMKi mice to induce and monitor skin tumors across five CIN levels in combination with DMBA/TPA treatment.

Low → more tumors but no effect on onset or growth
Moderate → more tumors earlier onset and larger growth
High → fewer tumors but earlier and earlier growth (2/5)

Altogether, our findings highlight the need to explore the tissue context of p53 responses to aneuploidy. We propose that future efforts should integrate the use of appropriate models of diverse healthy and pre-cancer human tissues.
(8/8)

Finally, we show that losses, but not gains, are more universally linked with p53 deficiency across cancer types. This association has been previously made and highlights an exciting direction to explore the role of p53 responses to aneuploidy.
(7/8)

Surprisingly, we find that neither arm-level or whole-chromosome CNAs correlate with p53 deficiency. This is particularly interesting given the role of p53 in responding to DNA damage, which is often linked to arm-level copy number alterations.
(6/8)

This lead us to ask the following question: can specific features of aneuploidy better distinguish p53 proficient and deficient tumors? To explore this we focused on the type (arm- or whole-chromosome) and direction of copy-number alteration (CNA).
(5/8)

We were excited to find that p53 inactivation is neither sufficient nor necessary for tumors to accumulate a high degree of aneuploidy. We find that tumors with high aneuploidy yet intact p53 are common, and also that p53 inactivation does not invariably lead to highly aneuploid tumors.
(4/8)

To fully capture the p53 status we defined p53 deficiency as either TP53 mutations or alterations that phenocopy TP53 loss. Aneuploidy was defined as arm- or whole-chromosome copy number alterations (CNAs).
(3/8)

Despite decades of research, it is still unclear whether p53 protects against particular forms of copy number alterations and whether it does so universally across cancer types. To investigate this we systematically analyzed TCGA tumors across 31 cancer types.
(2/8)