Cyclin D mediates tolerance of genome-doubling in cancers with functional p53.
Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidization, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53. We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events.



We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor. We characterized adapted and acute tetraploidization in a variety of flow cytometry and biochemical assays and tested our findings against human tumours through bioinformatics analysis of the TCGA dataset.



Cyclin D1 was found to be specifically overexpressed in early but not late passage tetraploid clones, and this overexpression was sufficient to promote tolerance to spontaneous and pharmacologically induced tetraploidy. We provide evidence that this role extends to D-type cyclins and their overexpression confers specific proliferative advantage to tetraploid cells. We demonstrate that tetraploid clones exhibit elevated levels of functional p53 and p21 but override the p53/p21 checkpoint by elevated expression of cyclin D1, via a stoichiometry-dependent and CDK activity-independent mechanism. Tetraploid cells do not exhibit increased sensitivity to abemaciclib, suggesting that cyclin D-overexpressing tumours might not be specifically amenable to treatment with CDK4/6 inhibitors.



Our study suggests that D-type cyclin overexpression is an acute event, permissive for rapid adaptation to a genome-doubled state in TP53 wild-type tumours and that its overexpression is dispensable in later stages of tumour progression.
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
A
A
Crockford
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
L P
LP
Zalmas
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
E
E
Grönroos
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
S M
SM
Dewhurst
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
N
N
McGranahan
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
M E
ME
Cuomo
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
V
V
Encheva
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
A P
AP
Snijders
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
J
J
Begum
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
S
S
Purewal
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
J
J
Cerveira
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
H
H
Patel
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
M J
MJ
Renshaw
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
C
C
Swanton
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000631:Aminopyridines / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D056745:Cyclin C / Q000096:biosynthesis / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003571:Cytochalasin B / Q000031:analogs & derivatives / Q000494:pharmacology; D004171:Diploidy; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D000631:Aminopyridines; D001562:Benzimidazoles; C503674:CCNC protein, human; C493956:CDKN1A protein, human; D056745:Cyclin C; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C024794:dihydrocytochalasin B; D003571:Cytochalasin B; C000590451:abemaciclib; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6