Cancer Reawakens Embryonic Gene Editors to Fuel Tumor Growth

Cancer cells are known to reawaken embryonic genes to grow. A new study reveals the disease also hijacks the proteins, or "editors", that control how those genes are read.

The findings, published today in the journal Nucleic Acids Research, help explain why tumors grow so fast and adapt so well, and may point the way to new treatments.

Embryonic cells have to grow fast and must be able to transform into many different tissue types. The cells rely on genetic programmes that are eventually switched off as tissues mature. Cancer reawakens these programmes, giving the disease embryonic-like potential to fuel growth.

Researchers at the Centre for Genomic Regulation (CRG) now show that cancer cells also alter the cell's editing tools to become embryo-like. These are splicing factors, proteins that edit RNA after it has been copied from DNA, rearranging different segments in the sequence so as to alter a gene's message.

Normally, splicing factors help cells adapt to changing environments by providing the ability to create different proteins from the same gene. The study found that cancer cells switch on splicing factors normally only active in early development, helping drive tumour growth.

We discovered that cancer doesn't invent brand-new tricks. Instead, it reuses old programs that cells normally use during early development, when fast growth is needed."

Dr. Miquel Anglada-Girotto, lead author of the study, Centre for Genomic Regulation

The researchers sketch out how cancer seizes control of the cell's gene editors. When cancer drivers are activated, in particular the notorious oncogene MYC, the balance of splicing factors is disrupted. The network is so tightly interconnected that disturbing just one part causes a ripple effect across the whole system.

When MYC or another cancer-initiating growth pathway is activated, it alters the behaviour of a handful of "initiator" editors, causing a chain reaction that switches on splicing factors that push cells to grow, while silencing the protective ones that normally hold growth in check.

"Combined with other faults that build up in the cell, this wholesale rewiring of splicing factors tips the balance from healthy growth to flipping the whole system into cancer-mode," explains Dr. Anglada-Girotto.

The research helps explain why cancer is such a formidable disease. It also suggests new opportunities. If doctors can detect when splicing factors begin to flip, they may spot cancers earlier. And if drugs can target just one splicing factor, it could ripple throughout the entire network and slow or stop tumour growth.

The discovery was made possible because researchers trained an artificial intelligence model to read the broad pattern of gene activity in cells and infer what the splicing factors were doing behind the scenes. Before, scientists had to read every tiny edit in every RNA molecule, a time-consuming and expensive process.

The authors of the study believe that with the new tool, researchers can now scan thousands of existing datasets to see how splicing factors behave, helping uncover how cancer seizes control of a cell and revealing hidden weak points.

The work was led by Dr. Anglada Girotto and supervised by ICREA Research Professor Luis Serrano at the Centre for Genomic Regulation and Dr. Samuel Miravet Verde at ETH Zurich.