Sendurai A. Mani and Robert
A. Weinberg talk with ScienceWatch.com and answer
a few questions about this month's New Hot Paper in the
field of Molecular Biology & Genetics.
Article Title: The epithelial-mesenchymal
transition generates cells with properties of
SA;Guo, W;Liao, MJ;Eaton, EN;Ayyanan, A;Zhou,
AY;Brooks, M;Reinhard, F;Zhang, CC;Shipitsin, M;Campbell,
LL;Polyak, K;Brisken, C;Yang,
Journal: CELL, Volume: 133, Issue: 4, Page: 704-715, Year:
MAY 16 2008
* Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA
* Whitehead Inst Biomed Res, Cambridge, MA 02142 USA.
(addresses have been truncated)
Why do you think your paper is highly
Currently, a number of groups are investigating the biology of tumor
initiation, invasion, and metastasis, as well as chemoresistance. Several
key factors that regulate these processes have been identified. The
aberrant activation of epithelial-to-mesenchymal transition (EMT) has been
linked with many of these processes during tumor progression.
In addition, recent findings have demonstrated that cancer stem cells also
play an important role in many of the above processes. Strikingly, we found
that epithelial cells that have undergone EMT not only appear mesenchymal
but also behave like stem cells. This finding completed a loop—EMT
plays a key role during cancer progression by generating cancer
stem cells—and touched upon many different
This work initiated a new set of questions that are currently being
answered by many new publications. In addition, our finding also
demonstrated that normal stem-like cells can be generated via EMT, which
links this finding to research related to normal cellular processes and
Does it describe a new discovery, methodology, or
synthesis of knowledge?
Our finding reports a new discovery. For the first time, our paper linked
two highly studied and seemly important processes during cancer
progression—EMT and cancer stem cells (CSC). Previously, these ideas
were believed to be completely independent processes.
Robert A. Weinberg
Our study showed that CSC is a state that can be generated from more
differentiate tumor cells instead of solely via the transformation of local
stem cells. Our finding also describes a new methodology. Specifically,
that one can generate large numbers of stem-like cells from differentiated
epithelial cells simply by inducing transient EMT.
Would you summarize the significance of your paper
in layman's terms?
Our body consists of two major types of cells, epithelial and mesenchymal.
The epithelial cells are tightly attached with one another and are less
migratory than mesenchymal cells, due to the continued presence of
cell-cell adhesion molecules. On the other hand, the mesenchymal cells are
loosely bound and are highly migratory.
In humans, more than 80% of all tumors originate in epithelial cells and
initially develop into benign tumors due to the continued expression of the
cell-cell adhesion molecules. In order to break away from these bonds and
become invasive and metastatic, epithelial cancer cells activate a normally
latent embryonic program known as EMT.
Recent findings have demonstrated that epithelial tumors (carcinomas)
contain multiple types of cancer cells, including both differentiated
cancer cells and cancer stem cells. CSCs can initiate the formation of
tumors with high efficiency as well as support the growth of the tumor
mass. These CSCs are also proposed to play an important role in metastatic
seeding and therapy resistance.
Previously, cells that have undergone EMT and CSCs were believed to
independently contribute to the diversity of different cell types within
tumors. However, we discovered that, through EMT, differentiated tumors can
These findings suggest that EMT may act as a central regulator of cancer
metastasis by not only enabling cancer cells to disseminate but also by
enabling the initiation of tumor growth in the new location. It also
suggests that activation of EMT may help to sustain primary tumor growth.
In addition, CSCs are resistant to numerous conventional therapies.
Therefore, the molecular mechanisms that regulate EMT could serve as novel
therapeutic targets for preventing tumor recurrence and treating resistant
How did you become involved in this research and
were there any problems along the way?
Bob Weinberg has created an excellent work environment where new
discoveries are extremely possible. He recruits people with different
expertise. He runs the lab like a Chairman of the Department, and his lab
members are like individual faculty members. He allows each researcher time
to develop their own idea, and he plays a key role in shaping their
findings into something novel.
He makes sure that researchers in his laboratory address key problems in
cancer biology, and that they meet other scientists in the field on a
regular basis. For example, Bob organizes weekly meetings with several
other MIT biologists, including Dr. Philip Sharp, Dr. Tyler Jacks, Dr.
Rudolph Jaenish, Dr. Frank Solomon, Dr. Jackie Lee, and several others.
At one of the meetings, someone from the Jaenish laboratory mentioned that
he could reprogram adult cells by modulating expression of genes in adult
cells. I immediately thought about the EMT process and felt there may be
some similarity whereby the EMT process may reprogram the adult epithelial
cell as well.
I went back to the lab and approached another postdoc, Dr. Mai-Jing Liao,
to help me to analyze some of my samples, which were induced to undergo
EMT. Mai-Jing did not believe that this was possible; however, he agreed to
help. To our surprise, we found that the cells that had undergone EMT
displayed stem cell properties.
Where do you see your research leading in the
Since EMT plays a very central role in promoting the spread of breast
cancer and the development of therapeutic resistance by cancer cells, tools
to identify the cells that have undergone EMT, and thus exhibit stem cell
properties, will improve our ability to predict the future spread of
This ability to identify patients whose cancer is likely to spread or
relapse will enable doctors to treat these patients accordingly, thereby
preventing the spread of the cancer. This finding should also lead to
development of new therapeutic options for eliminating these highly
aggressive cancer stem cells with the multiple traits necessary for
Our finding showed that large populations of CSCs or normal stem cells can
also be generated from differentiated normal/cancer cells, and this should
facilitate the study of CSC biology because large populations of CSC were
previously very difficult to obtain. For example, sufficient CSC can now be
obtained for the preclinical discovery necessary for the development of
compounds to selectively inhibit the growth of the drug-resistant CSC
Sendurai A. Mani, Ph.D.
Department of Molecular Pathology, Unit 951
University Of Texas
M. D. Anderson Cancer Center
Houston, TX, USA Web |
Robert A. Weinberg, Ph.D.
Whitehead Institute of Biomedical Research
Professor of Biology
Cambridge, MA, USA Web