Growing tissue stem cells into organoids and tumeroids: Predictive assay development

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Published: 26 Jun 2014
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Prof Hans Clevers - Hubrecht Institute, Utrecht, The Netherlands

Prof Clevers talks to ecancertv at WIN 2014 about using single stem cells to grow tissue for cancer research and potentially cancer treatment. 

What I spoke about is the following. A number of years ago we found out that the Wnt pathway drives colon cancer; it also drives the stem cells of the intestinal tract but the identity of those stem cells was unknown for a long time. By combining those two observations, Wnt drives cancer but Wnt drives healthy stem cells as well, we came up with a novel marker, LGR5, which is now widely used as a stem cell marker and LGR5 helped us to find the colon stem cell but also stem cells of many other tissues. So that was the starting point. We then realised that LGR5 is a receptor for a very potent growth factor called R-spondin and we designed cultures where we can take, we think, any type of stem cell from an adult mouse or human, culture it in a small cocktail of growth factors, the most important being R-spondin, and then have these single stem cells grow out for as long as we want.

Could you explain what organoids and tumeroids are?

Organoids are the small versions of organs that we grow from these stem cells, so colon organoids, we call them mini-guts, grow from a single stem cell taken from a colon. If you take a stem cell from the stomach you’ll grow a stomach organoid and the cells are quite dumb, they will make the tissue where they come from but they will never make anything else. Also important is that they only make the epithelium, they do not make the blood vessels or the immune cells, just the epithelium. Now, in cancer it is the epithelium that is actually the malignant tissue and a tumeroid would be an organoid not grown from a normal stem cell but grown from a cell that comes out of a tumour. Therefore it represents the tumour but then in a plastic dish.

What about the survival of organoids and tumeroids grown from single stem cells?

We’ve probably held the original ones in culture for 3-4 years so it looks like they grow indefinitely. Also when they are normal tissue people would have predicted that they would probably have to become cancer cells to grow for long times outside the body, that’s not what we find. We find that their genome stays entirely normal, telomeres stay long, people worry about short telomeres because that has to do with aging. We see no mutations, we see no structural changes to the chromosomes so it really looks like this is an indefinite culture of normal or malignant cells.

What are the potential applications of this research?

We’ve done a lot. We have, for instance, shown that you can treat mice with cultured stem cells, we’ve done that for colon and treated mice with colitis; we’ve done it for mice with liver diseases where we treat the mice with liver stem cells or liver mini-organs, that’s one thing, so regenerative medicine. We’ve even shown that you can take stem cells from a patient with cystic fibrosis, a little kid, grow them as a mini-gut, in the mini-gut repair the gene defect exactly. So there are three bases missing in this particular patient, put the three DNA bases back in the right gene and then grow a mini-gut out of that stem cell and the promise is that we would ultimately be able to give these cells back to a patient. But that has to go through a lot of regulatory hurdles. That would be one and a third one that’s of most interest to the people here is that we can grow mini-cancers from all of these different cancers that we talk about at the meeting and we can actually treat them in plastic with a variety of drugs and this could maybe predict the value of what patient to treat with what drug or maybe if you do trials, stratify the trials, say, “OK, these patients should go in arm A and these patients should go in arm B because they behave differently in these organoid cultures.” So it’s one important thing; actually we thought very hard about how to make this technology but also the tissues that we grow available to the academic and the industrial community. There are a lot of ethics involved that are very complicated because we sequence patients and their tumours, people know how to solve that, but we also grow patients’ tissue and their tumours and we don’t want to recreate a problem that has existed with healer cells where the original patient never had consented that T-cells were used and they were spread around the world. So we had to think very hard about protocols where we actually know exactly who has the cells at any time of the day and if a patient or the family of a patient wants the cells destroyed for whatever reason that we actually can force the people who are working with those cells to destroy the cells.

What is your overall take home message?

The take home message is that actually it is possible, against belief, that one can culture normal cells, normal stem cells, and malignant stem cells and it’s probably fast enough to build this in the clinical practice that we are now developing for cancer patients.