Scientists have demonstrated how restoring cellular memory prevents cancer cells’ ability to adapt to evade treatment. This is based on the specific way genetic material is organized in cells, which determines its ability to adapt to resist treatment.
Northwestern University biomedical engineers have doubled the effectiveness of chemotherapy in animal experiments. Instead of attacking cancer directly, the new approach prevents cancer cells from evolving to withstand treatment.
This makes the disease easier to target with existing drugs. In trials, the approach fully wiped out the disease to near completion in cellular cultures and it increased the effectiveness of chemotherapy in mouse models of human ovarian cancer.
Cancer has many distinctive features, but one trait underlies them all: its relentless ability to survive. Even as it is bombarded by the immune system and harsh medical treatments, cancer might shrink or slow its growth, but it rarely disappears. While genetic mutations contribute to this resistance, mutations occur much too slowly to explain cancer cells’ rapid survival response.
According to lead researcher Vadim Backman: “Cancer cells are great adapters…They can adapt to almost anything that’s thrown at them. First, they learn to evade the immune system. Then, they learn how to adapt to chemotherapy, immunotherapy and radiation. When they resist these treatments, they live longer and acquire mutations. We did not set out to directly kill cancer cells. We wanted to take away their superpower — removing their inherent abilities to adapt, to change and to evade.”
The researchers discovered a fundamental mechanism that explains this ability. The intricate organization of genetic material, called chromatin, dictates cancer’s ability to adapt and survive in the face of the most potent drugs.
Chromatin — a group of macromolecules including DNA, RNA and proteins — determines which genes are suppressed or expressed. To fit the two meters of DNA that comprises the genome within just one hundredth of a millimetre of space inside a cell’s nucleus, chromatin is packed extremely tight.
Imaging and modelling
Through a combination of imaging, simulations, systems modelling and in vivo experiments, the scientists discovered that the three-dimensional architecture of this packing not only controls which genes are expressed and how cells respond to stress, but it also allows cells to physically encode memories of gene transcription patterns into the geometry of the packing itself.
The genome’s 3D arrangement acts like a self-learning system, much like a machine learning algorithm. As it learns, this arrangement constantly reshapes into thousands of nanoscopic chromatin packing domains. Each domain stores part of a cell’s transcriptional memory, which dictates how the cell functions. Throughout one’s life, these cell-specific chromatin domains are formed, strengthened by cellular experiences, stored and rewritten. Problems with this transcriptional memory can lead to diseases such as cancer and Alzheimer’s disease and might even drive aging.
It was noted that when chromatin packing is disordered, a cell demonstrates more plasticity — or an increased ability to adapt — enabling them to learn to resist treatments such as chemotherapy.
The researchers developed a new computational model that uses physics to analyse how chromatin packing influences a cancer cell’s odds of survival against chemotherapy. After applying the new model to various types of cancer cells and chemotherapy drug classes, the team found it could accurately predict cell survival — before treatment even began.
Because chromatin packing is critical for cancer cell survival, the researchers wondered what might happen if they changed the packing architecture. Instead of developing new drugs, they screened hundreds of existing drug compounds to find candidates that could alter the physical environment inside cell nuclei to modulate chromatin packing. Ultimately, the team selected celecoxib, an FDA-approved anti-inflammatory drug that is already on the market. Often prescribed to treat arthritis and heart conditions, celecoxib has a side effect of altering chromatin packing.
New dugs for the future
Consequently, celecoxib and similar drugs could become a new class of compounds, called Transcriptional Plasticity Regulators (TPRs), designed to modulate chromatin conformation to prevent cancer cells’ adaptive abilities. The researchers found that combining celecoxib with standard chemotherapy caused a substantial increase in the number of cancer cells that died. The research appears in the journal Proceedings of the National Academy of Sciences.The research paper is titled: “Leveraging chromatin packing domains to target chemoevasion in vivo.”
