Cell News 04/2019
19
PRIZE WINNERS 2019
liver genetic disease, also recapitulated the ductal differentiation
defects observed on the patient tissue (9), thus establishing the
first human culture system for these diseases and suggesting
that the human organoid liver culture model could represent a
excellent tool not only to study liver diseases but also to screen
drugs for these diseases.
Along these lines, Primary Liver Cancer (PLC) is the second most
lethal malignancy worldwide and includes a heterogeneous
group of tumours with distinct histological features and poor
prognosis rates: hepatocellular carcinoma (HCC) represents 80%
of all PLCs, followed by cholangiocarcinoma (CC). A combined
hepatocellular-cholangiocarcinoma subtype (HCC/CC) accounts
for 0.4% to 14.2% of all PLCs. PLCs are characterized by a com-
plex and diverse landscape of genetic – including high degree of
aneuploidy, DNA copy number variations (CNV), somatic muta-
tions – and epigenetic alterations that drive neoplastic trans-
forma¬tion and growth (32), further supporting the need for
patient-tailored therapeutics, also called personalized medicine.
By adapting our human liver organoid culture protocol to human
primary liver cancer tissue, we successfully established primary
liver tumour organoids
in vitro
– called tumoroids – from tumour
resections (~1cm
3
tissue) of eight patients with PLC, including
its main three subtypes, HCC, CC and HCC/CC (33). The cultures
expanded long-term (~1 year), preserved the histological archi-
tecture, gene expression patterns and genetic alterations seen
in the patient tumour tissue of origin (Figure 4C). Importantly,
the tumoroids maintained most of the patient’s tissue-of-origin
traits, namely their genetic aberrations, metastatic potential
and expression profile. Interestingly, we used liver tumoroids
to tested for their potential as a platform for drug screening
and validation of candidate therapies and found that tumoroids
responded with varying levels of sensitivity (33), supporting their
use as platform for drug sensitivity testing in a patient-specific
manner, opening the doors for precision oncology. The impact of
the different sensitive compounds in healthy tissue remains to
be tested yet this could easily be achieved using healthy organ-
oids. Unfortunately, we were unable to establish tumoroids from
very well differentiated tumours (with less than 5% of prolifer-
ating cells), precluding drug testing for less advanced tumours
(33). Whether refining the medium conditions may facilitate the
establishment of tumoroids from very well differentiated tu-
mours remains to be determined. In addition, whether tumoroids
may also help identify therapies for tumours with metastases
remains to be investigated.
Outlook
In conclusion, liver organoids derived from embryonic or adult
healthy or diseased tissue are providing excellent opportunities
to study human liver in an unprecedented manner. Parallel to
furthering our fundamental understanding of liver development,
biology and disease, human liver organoids excel as promising
tools for a wide range of biomedical applications from disease
modelling of rare disorders to personalized medicine. In addition,
not only could organoids be used for drug testing, but there is
an increasing use of liver organoids and liver-on-a-chip models
to test drug metabolism. Similarly, liver organoid technologies
could be applied to cell replacement or even whole-organ trans-
plantation. While still far from being a reality, and significant
improvements on the technology are still required to achieve
this goal, we envision the field driving into this type of applica-
tion in the future.
Acknowledgements
I would like to thank all (present and past) members of my lab
for their excellent work and enthusiasm and being excellent
colleagues to work with, with fantastic personalities that have
made my role of supervisor a very easy task. Additionally, I
would like to thank my mentors that through the years have
supported me either personally or professionally, including
Prof Hans Clevers, Prof Andrea Brand, Prof Anna Philpott, Prof
Magdalena Zernicka-Goetz, Prof Ben Simons and, more recently,
Prof Marino Zerial. Also, research in my lab has been funded by
a Wellcome Trust Sir Henry Dale Fellowship from the Wellcome
trust and Royal Society, awarded to me on 2014 to establish my
own lab in Cambridge (104151/Z/14/Z). My lab has also been
funded by an NC3Rs Program grant and a H2020 collaborative
grant (LSMF4LIFE).
References
1 Lancaster MA, Knoblich JA. Organogenesis in a dish: Mod-
eling development and disease using organoid technologies.
Science (80- )
2014;
345
:1247125–1247125. doi:10.1126/
science.1247125
2 Huch M, Koo B-K. Modeling mouse and human development
using organoid cultures.
Development
2015;
142
:3113–25.
doi:10.1242/dev.118570
3 Smith E, Cochrane WJ. Cystic organoid teratoma: (Report of a
Case).
Can Med Assoc J
, 1946;
55
: 151-2.
4 Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build
crypt-villus structures in vitro without a mesenchymal niche.
Nature
2009;
459
:262–5. doi:10.1038/nature07935
5 Barker N, Huch M, Kujala P, et al. Lgr5(+ve) stem cells drive
self-renewal in the stomach and build long-lived gastric
units in vitro.
Cell Stem Cell
2010;
6
:25–36. doi:10.1016/j.
stem.2009.11.013
6 Huch M, Bonfanti P, Boj SF, et al. Unlimited in vitro expan-
sion of adult bi-potent pancreas progenitors through the
Lgr5/R-spondin axis.
EMBO J
2013;
32
:2708–21. doi:10.1038/
emboj.2013.204
7 Boj SF, Hwang CI, Baker LA, et al. Organoid models of human
and mouse ductal pancreatic cancer.
Cell
2015;
160
:324–38.
doi:10.1016/j.cell.2014.12.021
8 Huch M, Dorrell C, Boj SF, et al. In vitro expansion of single
Lgr5+ liver stem cells induced by Wnt-driven regeneration.
Nature
2013;
494
:247–50. doi:10.1038/nature11826
9 Huch M, Gehart H, van Boxtel R, et al. Long-Term Culture of
Genome-Stable Bipotent Stem Cells from Adult Human Liver.
Cell
2015;
160
:299–312. doi:10.1016/j.cell.2014.11.050
