Longevity Briefs: Reprogramming Cancer Cells To Be Normal Again

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Currently, the only way to cure someone of cancer is to remove or kill all of the cancer cells. Unfortunately, treatments like chemotherapy or radiotherapy are also toxic to normal cells, and can damage them in such a way that they are more likely to become cancerous in the future. This is one of the reasons why cancer is much more likely to occur in someone who has already had cancer before.

What if, instead of killing cancer cells, we could turn them back into normal cells? Cancer occurs as a result of a series of genetic mutations that are accumulated over time, but there nevertheless seems to be a period of time – a ‘critical transition’ – at which a cell becomes cancerous. In this study, researchers investigate exactly what is happening during this critical transition period, in the hope that it may hold clues to reversing it.

The discovery:

Researchers first produced organoids containing both human colorectal cancer cells and normal cells. Organoids are miniature organs or tissues composed of cells that are capable of organising together in cell culture. They then used genetic sequencing data in order to deduce the evolutionary trajectory of the tumour, identifying subgroups sharing a common ancestor in which cancer cells and non-cancer cells coexisted. This coexistence marked these cells as being in an unstable transition state.

They then developed a technology called REVERT that can take sequencing data from these transition cells and use it to generate a computer model of the genetic network that controls the transition between normal and cancer cells. This model was then used to simulate the overexpression or knockout of different combinations of transcription factors (molecules that regulate gene expression) in order to predict which ones might act as ‘reversion switches’ to reverse the transition into cancer cells.

Finally and most importantly, the researchers validated their model by targeting one of these reversion switches called USP7, a gene that codes for an enzyme that stabilises a number of proteins involved in cancer survival. When the colorectal cancer organoids were treated with P22077, an inhibitor of USP7, the growth of the organoids was significantly slowed, and the overall genetic signature of the organoids changed to one that was less cancer-like.

The implications:

This kind of technology could be used in the future to identify targets for cancer reversion, resulting in personalised treatments to be used alongside existing cancer therapies. It remains to be seen whether complete reversion occurs in cells that are still in the critical transition phase, and whether later cancer descendants can also be reprogrammed into normal cells.

The idea that cancer cells can be reprogrammed into normal cells through genetic manipulation isn’t new. By exposing a cell to a cocktail of transcription factors known as Yamanaka factors, it is possible to erase its ‘identity’ (as heart cell, brain cell and so on) and turn it back into a stem cell. This also works on cancer cells, turning them into non-cancerous stem cells. However, turning every cell in a person’s tumour into a stem cell would be a pretty bad idea, which is why targeted approaches to reprogramming like this one or, alternatively, partial reprogramming, will be necessary. To learn more about partial reprogramming and how it might be used to treat not only cancer but ageing in general, take a look at this article.