Chromosome abnormalities may help cancer cells resist treatment and spread

A new study led by NYU Langone Health researchers found that cancer cells are better able to resist treatments when they have an abnormal number of chromosomes, which are DNA strands wound up in bundles that control which genetic instructions are followed in each cell type.

As a cell gets ready to divide into two cells as part of growth, mechanisms exist to ensure each resulting cell gets its proper share of DNA packaged in chromosomes. The abnormal, too-frequent cell division seen in tumor growth, however, leads to random copying errors that frequently change the chromosome number per cell.

The new work suggests that abnormal chromosome numbers (aneuploidy) in cancer cells represent a previously unknown mechanism that helps them resist treatment. Cancers with more chromosome errors are known to be more aggressive, but the mechanisms behind the pattern have been poorly understood, the study authors say.

Published online May 7 in Molecular Cell, the work found that cancer cells with extra or missing chromosomes have 50 to 60 percent less than the normal amount of a protein called Poly (ADP-Ribose) Polymerase 1 (PARP1).

PARP1 normally triggers a type of cell death when DNA damage from reactive oxygen species—highly reactive molecules that can damage DNA—becomes too severe, in a process called oxidative stress. With less PARP1, cancer cells with aneuploidy better survive stress that would kill normal cells, the same stress created by cancer treatments.

"A better understanding of how aneuploidy impacts tumor formation could drive the development of new kinds of therapies," says senior study author Teresa Davoli, PhD, an associate professor in the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health and member of the faculty at the Institute for Systems Genetics. "Our findings suggest that having the wrong number of chromosomes rewires both how cancer cells grow and how they spread."

How chromosome errors protect cancer cells

The research team created laboratory models of aneuploidy using human cells from the colon, lung, and eye. They introduced chromosome errors through standard methods and then exposed these cells to reactive oxygen species. Across every model, cells with abnormal chromosome counts survived better than normal cells, regardless of whether chromosomes were gained or lost.

For the study, the team tested inhibitors of several cell death pathways, but only those blocking PARP1 rescued normal cells from oxidative stress. PARP1 is an enzyme that normally detects and helps to repair DNA damage, but when overactivated by severe damage, kills the now-flawed cells to keep them from multiplying. The researchers confirmed across 15 cell models that aneuploid cells consistently produce roughly half as much PARP1, disabling this self-destruct mechanism and letting cancer cells thrive.

The team then used a genome-wide CRISPR screen—a method that systematically tests every gene in the genome to find which control PARP1 levels. They discovered that chromosome errors cause stress in lysosomes, the cell's recycling centers, which activates a protein called CCAAT/enhancer-binding protein beta (CEBPB), which dials down PARP1 production.

In mouse experiments, lowering PARP1 helped cancer cells spread to distant organs, while raising PARP1 reduced that ability. Human tumor data confirmed that metastatic colorectal cancers had lower PARP1 than primary tumors.

"We now want to explore whether restoring PARP1 activity or targeting this stress response pathway could slow cancer spread," says first author Pan Cheng, PhD, a former PhD student in Dr. Davoli's lab. "We also plan to investigate whether aneuploidy-driven PARP1 loss affects how patients respond to existing cancer drugs, including PARP inhibitors already in use."

Along with Drs. Davoli and Cheng, study authors from the Institute for Systems Genetics were Angela Mermerian-Baghdassarian, Yufeng Wang, Ze Chen, Helberth Quysbertf, Joseph Mays, Xin Zhao, Lizabeth Katsnelson, Sally Mei, and Rohini Shrivastava.

Also authors were Jiehui Deng, PhD, and Kwok-Kin Wong, MD, PhD, in the Division of Hematology and Medical Oncology, the clinical arm of NYU Langone's Perlmutter Cancer Center; and Pradeep Singh Cheema and Markus Schober, PhD, of the Ronald O. Perelman Department of Dermatology. Mirna Bulatovic of Loxo Oncology at Lilly was also an author. Pan Cheng, PhD, is now a postdoctoral fellow in the lab of Charles Sawyers at Memorial Sloan Kettering Cancer Center.

This research was supported by National Institutes of Health grants R37 R37CA248631, R01 R01HG012590, R01 R01DK135089, along with support from the Cancer Research UK Grand Challenge, the Mark Foundation for Cancer Research (C5470/A27144), the National Foundation for Cancer Research, Perlmutter Cancer Center Support Grant P30CA016087, NYU Langone's Genome Technology Center (RRID:SCR_017929) and Proteomics Laboratory (RRID:SCR_017926), an MRA Young Investigator Award, the Breast Cancer Alliance Young Investigator Award, a Pershing Square Sohn Cancer Research Award, and a V Foundation Scholar Award.