Aneuploidy is a hallmark of cancer with tissue-specific prevalence patterns that suggest it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on both cellular and genomic contexts. Whole-genome duplication (WGD) is a common macroevolutionary event that occurs in more than 30% of human tumors early in tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy, it remains unknown whether WGD also affects aneuploidy prevalence patterns. Here we analyzed clinical tumor samples from 5,586 WGD− tumors and 3,435 WGD+ tumors across 22 tumor types and found distinct patterns of aneuploidy in WGD− and WGD+ tumors. WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD− and WGD+ tumors, giving rise to distinct cooccurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy compared with arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Finally, induction of WGD and assessment of aneuploidy in isogenic WGD−/WGD+ human colon cancer cell lines under standard or selective conditions validated key findings from the clinical tumor analysis, supporting a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors and propose that this interaction contributes to tumor evolution. Significance: These findings suggest that the interactions between whole-genome duplication and aneuploidy are important for tumor evolution, highlighting the need to consider genome status in the analysis and modeling of cancer aneuploidy.

Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We use patient-derived glioma stem cells and human glial cells (i.e., astrocytes and microglia) to create a four-component 3D model of this environment informed by resected patient tumors. We examine metrics for invasion, proliferation, and putative stemness in the context of glial cells, fluid forces, and chemotherapies. While the responses are heterogeneous across seven patient-derived lines, interstitial flow significantly increases glioma cell proliferation and stemness while glial cells affect invasion and stemness, potentially related to CCL2 expression and differential activation. In a screen of six drugs, we find in vitro expression of putative stemness marker CD71, but not viability at drug IC₅₀, to predict murine xenograft survival. We posit this patient-informed, infiltrative tumor model as a novel advance toward precision medicine in glioblastoma treatment.

Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally very different compared to the healthy cells from which they evolved. Genomic alterations include aneuploidy (numerical and structural changes in chromosome content) and polyploidy (e.g., whole genome doubling), which can have considerable effects on cell physiology and phenotype. Likewise, conditions in the tumor microenvironment are spatially heterogeneous and vastly different than in healthy tissues, resulting in a number of environmental niches that play important roles in driving the evolution of tumor cells. While a number of studies have documented abnormal conditions of the tumor microenvironment and the cellular consequences of aneuploidy and polyploidy, a thorough overview of the interplay between karyotypically abnormal cells and the tissue and tumor microenvironments is not available. Here, we examine the evidence for how this interaction may unfold during tumor evolution. We describe a bidirectional interplay in which aneuploid and polyploid cells alter and shape the microenvironment in which they and their progeny reside; in turn, this microenvironment modulates the rate of genesis for new karyotype aberrations and selects for cells that are most fit under a given condition. We conclude by discussing the importance of this interaction for tumor evolution and the possibility of leveraging our understanding of this interplay for cancer therapy.

An increase in centrosome number is commonly observed in cancer cells, but the role centrosome amplification plays along with how and when it occurs during cancer development is unclear. One mechanism for generating cancer cells with extra centrosomes is whole genome doubling (WGD), an event that occurs in over 30% of human cancers and is associated with poor survival. Newly formed tetraploid cells can acquire extra centrosomes during WGD, and a generally accepted model proposes that centrosome amplification in tetraploid cells promotes cancer progression by generating aneuploidy and chromosomal instability. Recent findings, however, indicate that newly formed tetraploid cells in vitro lose their extra centrosomes to prevent multipolar cell divisions. Rather than persistent centrosome amplification, this evidence raises the possibility that it may be advantageous for tetraploid cells to initially restore centrosome number homeostasis and for a fraction of the population to reacquire additional centrosomes in the later stages of cancer evolution. In this review, we explore the different evolutionary paths available to newly formed tetraploid cells, their effects on centrosome and chromosome number distribution in daughter cells, and their probabilities of long-term survival. We then discuss the mechanisms that may alter centrosome and chromosome numbers in tetraploid cells and their relevance to cancer progression following WGD.

A biophysical model was developed for centrosome movement during mitotic–spindle assembly to investigate how a cell manages to separate and cluster its centrosomes depending on needs to achieve bipolar spindle formation. The model provides explanation for related experimental phenomena and mechanistic insights into robust spindle bipolarization.

Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. Whereas the genomic consequences of WGD are well documented, nongenetic alterations that accompany WGD, such as changes to cell and nuclear size, may also play an important role in tetraploid (4N) cancer cell physiology. In this study, we showed that cell and nuclear volume does not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. Small size was associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size may contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD. Significance: Cancer cell size varies after whole genome duplication, with smaller cells exhibiting high tumorigenicity and correlating with poor patient survival, demonstrating the clinical relevance and highlighting the biomarker potential of cell size.