Biology subjects

Spierings, D. C.

Publications and source records attributed to Spierings, D. C..

3 recordsLinked to original sources

bioRxiv2023

Predicting CIN rates from single-cell whole genome sequencing data using an in silico model

Chromosomal instability (CIN) drives the formation of karyotype aberrations in cancer cells and is a major contributor to intra-tumour heterogeneity, metastasis, and therapy resistance. Understanding how CIN contributes to tumour karyotype evolution requires quantification of CIN rates in primary tumours. Single-cell sequencing-based technologies enable the detection of karyotype heterogeneity, however deducing the actual CIN rates that underlie intra-tumour heterogeneity is still complicated. We have developed an in-silico model, called CINsim, to simulate the karyotype dynamics and validated our model in a murine mouse model for T-cell lymphoma (T-ALL) in which CIN is introduced by mutation of the Mps1 spindle assembly checkpoint protein. CINsim can simulate karyotype evolution within physiologically relevant timescales, across a range of CIN rates, and across a range of karyotype-imposed survival and proliferation effects. We find that CINsim can accurately predict the CIN rates in chromosomal instable mouse T-ALLs as well as in human colon cancer organoids as observed by live-cell time-lapse imaging. We conclude that CINsim is a powerful tool to estimate CIN rates from static single-cell DNA sequencing data by finding the most likely path from euploid founder cell to a heterogeneous tumour cell population.

cancer biology↗

bioRxiv2022

Molecular origins of genome instability following a single chromosome mis-segregation event

Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures were upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.

cell biology↗

bioRxiv2020

Transient genomic instability drives tumorigenesis through accelerated clonal evolution

Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we compared tumor development in mice with chronic chromosome instability (CIN) induced by inactivation of the spindle assembly checkpoint (produced by Mad2 deficiency) and mice with transient CIN through transiently increased expression of polo-like kinase 4 (PLK4), a master regulator of centrosome number. Tumors forming under chronic CIN gradually trended toward chromosomal gains producing a specific karyotype profile that could only be partially maintained in end-stage tumors, as determined by single-cell whole genome DNA sequencing. Short term CIN from transient PLK4 induction generated significant centrosome amplification and aneuploidy resulting in formation of aggressive T cell lymphomas in mice with heterozygous inactivation of one p53 allele or accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphomainitiating cells (as revealed by T cell receptor sequencing) with a specific karyotype profile containing triploid chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Overall, our evidence demonstrates that distinct CIN mechanisms drive cancers presenting specific, complex chromosomal alterations with transient CIN rapidly enhancing tumor formation by accelerating the generation of such events.

cancer biology↗