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CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11th International Conference on
Journal of Medical Oncology and Therapeutics | Volume 3
Frederic Hollande, J Med Oncl Ther 2018, Volume 3
ROLE OF miRNAS AND YAP IN THE
PROMOTION OF COLORECTAL CANCER
STEM CELL SELF-RENEWAL BY THE
TIGHT JUNCTION PROTEIN CLAUDIN-2
Frederic Hollande
The University of Melbourne, Australia
Colorectal cancer (CRC) is the third most lethal cancer worldwide,
often due to post-treatment recurrence driven by a subpopulation
of Cancer Stem Cells (CSCs). The tight junction (TJ) protein claudin-2
is overexpressed in human CRC, where it enhances cell proliferation,
colony formation and chemoresistance in vitro. While several of these
biological processes are features of the CSC phenotype, a putative role for
claudin-2 in the regulation of these had hitherto not been explored. Here,
we identify that elevated claudin-2 expression in stage II/III colorectal
tumors is associated with poor recurrence-free survival after 5-FU-based
chemotherapy, an outcome in which CSCs play an instrumental role.
Using overexpression and/or down-regulation models in patient-derived
organoids, primary cells and cell lines, we show that claudin-2 promoted
CRC self-renewal in vitro and in multiple mouse xenograft models.
Claudin-2 enhanced self-renewal of ALDHHigh CSCs and increased
their proportion in CRC cell populations, limiting their differentiation and
promoting the phenotypic transition of non-CSCs towards the ALDHHigh
phenotype. Using Next Generation Sequencing in ALDHHigh cells, we
establish that claudin-2 regulated the expression of several microRNAs
known to control stem cell signalling. We demonstrate that, among
these, miR-222-3p was instrumental for the regulation of self-renewal
by claudin-2. We also found that the enhancement of self-renewal by
claudin-2 required the activation of YAP, most likely upstream from miR-
222-3p. Taken together, our results indicate that overexpression of the
TJ protein claudin-2 promotes self-renewal within CRC stem-like cells,
suggesting a potential role for this protein as a therapeutic target in CRC.
Frederic Hollande has completed his PhD in
1994 at the University of Montpellier, France. He
worked as a Post-doctoral Research Fellow at
the Ludwig Institute for Cancer Research and
the University of Melbourne, and was recruited
as a Research Fellow by the French National
Centre for Scientific Research (CNRS) in 1996.
He became Group Leader in 2000 and Head of
the Oncology Research Department at the Insti-
tute of Functional Genomics (IGF) of Montpel-
lier in 2011. In 2007, he co-founded a Biotech
Company (colon cancer therapeutics) and was
the Joint-Scientific Director until 2011. He has
been an Associate Professor in the Department
of Pathology at the University of Melbourne
since September 2012. His laboratory is located
at the new purpose-built Victorian Comprehen-
sive Cancer Centre in Melbourne. His research
interest lies in the study of tumour heterogene-
ity and the regulation of cancer stem cells in col-
orectal and other cancers
BIOGRAPHY