Biology subjects

Rancati, G.

Publications and source records attributed to Rancati, G..

4 recordsLinked to original sources

bioRxiv2021

Whole-genome duplication shapes the aneuploidy landscape of human cancers

Aneuploidy - a hallmark of cancer - has tissue-specific recurrence patterns suggesting it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on the cellular and genomic context in which it arises. Whole-genome duplication (WGD) is a common macro-evolutionary event that occurs in >25% of human tumors during the early stages of tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy than tumors that have not, it remains unknown whether WGD affects aneuploidy recurrence patterns in human cancers. Here we analyzed clinical tumor samples from 449 WGD- tumors and 157 WGD+ tumors across 22 tumor types. We found distinct recurrence patterns of aneuploidy in WGD- and WGD+ tumors. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct co-occurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy vs. arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation in WGD- and WGD+ tumors. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Lastly, we induced WGD in human colon cancer cell lines, and followed aneuploidy formation in the isogenic WGD+/WGD-cells under standard or selective conditions. These experiments validated key findings from the clinical tumor analysis, and revealed a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors, and propose that the interaction between WGD and aneuploidy is a major contributor to tumor evolution.

cancer biology↗

bioRxiv2020

Epistasis, aneuploidy, and gain-of-function mutations underlie the evolution ofresistance to induced microtubule depolymerization

Microtubules, polymers of alpha- and beta-tubulin, are essential cellular components. When microtubule polymerization is hindered, cells are delayed in mitosis, but eventually they manage to proliferate with massive chromosome missegregation. Several studies have analyzed the first cell division upon microtubules impairing conditions. Here, we asked how cells cope on the long term. Taking advantage of mutations in beta-tubulin, we evolved in the lab for [~]150 generations 24 populations of yeast cells unable to properly polymerize microtubules. At the end of the evolution experiment, cells re-gained the ability to form microtubules, and were less sensitive to microtubule depolymerizing drugs. Whole genome sequencing allowed us to identify genes recurrently mutated (tubulins and kinesins) as well as the pervasive duplication of chromosome VIII. We confirmed that mutations found in these genes and disomy of chromosome VIII allow cells to compensate for the original mutation in beta-tubulin. The mutations we identified were mostly gain-of-function, likely re-allowing the proper use of the mutated form of beta-tubulin. When we analyzed the temporal order of mutations leading to resistance in independent populations, we observed multiple times the same series of events: disomy of chromosome VIII followed by one additional adaptive mutation in either tubulins or kinesins. Analyzing the epistatic interactions among different mutations, we observed that some mutations benefited from the disomy of chromosome VIII and others did not. Given that tubulins are highly conserved among eukaryotes, our results are potentially relevant for understanding the emergence of resistance to drugs targeting microtubules, widely used for cancer treatment.

cell biology↗

bioRxiv2020

CENP-A chromatin prevents replication stress at centromeres to avoid structural aneuploidy

Chromosome segregation relies on centromeres, yet their repetitive DNA is often prone to aberrant rearrangements under pathological conditions. Factors that maintain centromere integrity to prevent centromere-associated chromosome translocations are unknown. Here, we demonstrate the importance of the centromere-specific histone H3 variant CENP-A in safeguarding DNA replication of alpha-satellite repeats to prevent structural aneuploidy. Rapid removal of CENP-A in S-phase, but not other cell cycle stages, caused accumulation of R-loops with increased centromeric transcripts, and interfered with replication fork progression. Replication without CENP-A causes recombination at alpha-satellites in an R-loop-dependent manner, unfinished replication and anaphase bridges. In turn, chromosome breakage and translocations arise specifically at centromeric regions. Our findings provide insights into how specialized centromeric chromatin maintains the integrity of transcribed noncoding repetitive DNA during S-phase. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/277103v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@4e6dc4org.highwire.dtl.DTLVardef@1089c90org.highwire.dtl.DTLVardef@5ee5c2org.highwire.dtl.DTLVardef@3e300d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

p53 induces senescence in the unstable progeny of aneuploid cells

Aneuploidy is the condition of having an imbalanced karyotype, which is strongly associated with tumor initiation, evolution, and acquisition of drug-resistant features, possibly by generating heterogeneous populations of cells with distinct genotypes and phenotypes. Multicellular eukaryotes have therefore evolved a range of extrinsic and cell-autonomous mechanisms for restraining proliferation of aneuploid cells, including activation of the tumor suppressor protein p53. However, accumulating evidence indicates that a subset of aneuploid cells can escape p53-mediated growth restriction and continue proliferating in vitro. Here we show that such aneuploid cell lines display a robust modal karyotype and low frequency of chromosomal aberrations despite ongoing chromosome instability. Indeed, while these aneuploid cells are able to survive for extended periods in vitro, their chromosomally unstable progeny remain subject to p53-induced senescence and growth restriction, leading to subsequent elimination from the aneuploid pool. This mechanism helps maintain low levels of heterogeneity in aneuploid populations and may prevent detrimental evolutionary processes such as cancer progression and development of drug resistance.

cancer biology↗