Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

Abstract

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy is typically detrimental to cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to a variety of different culture environments. While chromosomal instability was universally detrimental under normal growth conditions, we discovered that transient CIN reproducibly accelerated the ability of cells to adapt and thrive in the presence of anti-cancer therapeutic agents. Single-cell sequencing revealed that these drug-resistant populations recurrently developed specific whole-chromosome gains and losses. We independently derived one aneuploidy that was frequently recovered in cells exposed to paclitaxel, and we found that this chromosome loss event was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to a variety of systemic therapies in a collection of patient-derived xenografts. In total, our results show that while chromosomal instability generally antagonizes cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure in human tumors.

Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment

“…In a mouse model, low-to-moderate levels of CIN were found to promote tumorigenesis, while high levels of CIN suppressed tumor progression [ 163 ]. As a result of these observations, it has been proposed that exacerbating CIN beyond a tolerable level may be a viable therapeutic strategy [ 190 ], but such an approach should be considered with caution [ 191 , 192 ].…”

“…Direct gain of 4q may not have been favorable in this context because it harbors numerous tumor suppressor genes, indicating that genetic interactions between specific aneuploidies and other chromosomes influence karyotype evolution (as reported in yeast [ 301 ]). In a similar study, recurrent aneuploidies were also detected in various cell lines following Mps1 disruption and drug pressure; however, the observed karyotypic changes were unique for each cell line used even when challenged with the same drug [ 191 ]. Although the mechanisms underlying resistance were not identified in this study, the unique karyotypic routes to drug resistance across cell types demonstrate there are multiple genomic paths to a given phenotype (drug resistance) and the cell’s genomic and/or epigenetic background is an important factor for the observed effects of chromosomal alterations.…”

“…Furthermore, tetraploidy increased the resistance of non-transformed RPE-1 cells and HCT-116 CRC cells to a variety of chemotherapeutic drugs [ 171 ]. The effects of WGD may depend on the genetic background and/or mechanism of tetraploidization, as drug-induced mitotic slippage in PC9 lung cells did not promote resistance to the EGFR inhibitor gefitinib [ 191 ]. WGD can also render cells vulnerable to specific genetic challenges, such as impairment of DNA replication, proteasome inhibition, and KIF18A depletion [ 313 ].…”

Quantifying chromosomal instability from intratumoral karyotype diversity using agent-based modeling and Bayesian inference

“…Importantly, CIN potentiates tumorigenesis (Foijer et al, 2017;Levine et al, 2017;Silk et al, 2013) and associates with therapeutic resistance (Ippolito et al, 2020;Lee et al, 2011;Lukow et al, 2020;Pavelka et al, 2010), metastasis (Bakhoum et al, 2018) and poor survival outcomes (Bakhoum et al, 2011;Denu et al, 2016;Jamal-Hanjani et al, 2017). Thus, CIN is an important characteristic of cancer biology.…”

“…These observations highlight the confounding role of karyotype selection in measuring CIN in human tumors. Indeed, karyotype selection reduces karyotype variance in cancer cell populations, even after exhibiting mitotic errors (Gerstung et al, 2020;Ippolito et al, 2020;Lukow et al, 2020). It may be possible to overcome this limitation by modeling chromosomal instability and explicitly considering the evolutionary selection of aneuploid cells.…”