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, the 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 tumour growth, however, leads to 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 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 tumour 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 faculty in 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 colon, lung, and eye cells.

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 centres, 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 tumour data confirmed that metastatic colorectal cancers had lower PARP1 than primary tumours.

"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."

Source: NYU Langone Health / NYU Grossman School of Medicine