Pan European Networks - Horizon 2020 - page 204

enhancement of TARBP2 activity by the fluoroquinolone enoxacin leads
to restoration of miRNA maturation and the elimination of CSC
properties. More recently, we found that a combination of enoxacin with
standard of care chemotherapy reverses Ewing’s sarcoma growth in
preclinical
in vivo
models. These observations provide insight into the
effect of an approach designed to target two critical cell populations in
a malignant tumour: CSCs and the tumour bulk. By inducing CSC
differentiation as a result of miRNA expression that abrogates stemness,
the tumour loses its primary driving force, without which the bulk of
the cells cannot be maintained. Simultaneous targeting of the bulk
cell population reduces the likelihood of reprogramming of non-
tumourigenic cells to form new CSCs.
At the Institute of Pathology at Lausanne University Hospital, we are using
novel approaches to identify CSCs in other sarcoma types, including ones
that do not have specific chromosomal translocations and where cell
surface CSC markers are unknown or absent. Tumour cell heterogeneity
is seen in most solid malignancies. The identification of the
subpopulations of cells that constitute the tumour’s driving force will be
an important factor in defining novel and effective mechanism-based
therapeutic strategies.
S
arcomas are malignant tumours of bone and soft tissues that
comprise about 2% of all human malignancies but as much as
15% of paediatric cancers. Despite aggressive multimodal therapy,
most sarcomas retain poor prognosis with a high recurrence rate of
metastatic proclivity. Sarcoma biology is still poorly understood, and much
remains to be learned regarding mechanisms that lead to such tumours’
development and relevant candidate therapeutic targets.
We have undertaken studies aimed at identifying the cell of origin of a
variety of sarcomas with the goal of elucidating the carcinogenic events
that lead to primary cell transformation and subsequent development of
malignant tumours with the ability to metastasise. We have shown that
bone marrow-derived mesenchymal stem cells (MSC) are cells of origin
of Ewing’s sarcoma, the second most common bone malignancy of
children and young adults, and of myxoid liposarcoma, which is more
commonly an adult tumour. However, there is increasing evidence that
other sarcomas, including osteosarcoma and synovial sarcoma, also
originate in MSC subsets.
Ewing’s sarcoma
Our observations led us to address mechanisms whereby MSCs become
transformed to develop Ewing’s sarcoma. We found that the fusion gene,
EWS-FLI1, which arises as a result of a specific chromosomal
translocation and is characteristic of Ewing’s sarcoma, induces epigenetic
modifications that reprogramme permissive MSCs and lead to
transformation with acquisition of stem cell properties.
The observed reprogramming occurs because of modifications that
include changes in chromatin structure which alter the expression of key
genes that regulate cell survival and proliferation, as well as changes in
expression of small non-coding RNAs, known as microRNAs (miRNAs),
that control the expression of entire networks of genes. We were able to
show that modulation of the miRNA expression profile in MSCs leads to
the emergence of cancer stem cells (CSC) in Ewing’s sarcoma.
Cancer stem cells are believed to constitute the driving force in most
malignancies in that they have the ability to self-renew and to give rise
to more differentiated cancer cell progeny that constitutes the tumour
bulk. Partly because CSCs divide slowly, they are relatively unharmed by
conventional anticancer therapies, which are aimed at eliminating rapidly
proliferating cells. We have identified CSCs in primary Ewing’s sarcoma
and are currently pursuing experiments to understand how CSCs develop
from primary cells.
Suppressing TARBP2
We have uncovered a mechanism whereby CSCs in Ewing’s sarcoma
are formed and maintained. The mechanism in question depends on
partial suppression of the protein TARBP2, which plays a central role in
the maturation of a broad spectrum of miRNAs. We have shown that
Ewing’s sarcoma source
As
Professor Ivan Stamenkovic,
of Lausanne University Hospital, discusses,
bone marrow-derived mesenchymal stem cells are the origin of the cancerous
tumour Ewing’s sarcoma
204
I S S U E S I X
H O R I Z O N 2 0 2 0 P R O J E C T S : P O R TA L
O N C O L O G Y
Ewing’s sarcoma in lung
© Nephron
Professor Ivan Stamenkovic
Lausanne University Hospital
B R OW S E
H O R I Z O N
2 0 2 0
1...,194,195,196,197,198,199,200,201,202,203 205,206,207,208,209,210,211,212,213,214,...244
Powered by FlippingBook