Cancer Cell

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Hijacking EMT: Better Fat Than Dead

Stefan Hinz1 and Mark A. LaBarge1,*
1Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA

*Correspondence: mlabarge@coh.org
https://doi.org/10.1016/j.ccell.2018.12.007

Potential for cancers to form metastases requires cell dissemination utilizing epithelial-to-mesenchymal
transition (EMT) program. In this issue of Cancer Cell, Ishay-Ronen et al. show that plasticity intrinsic to
the EMT program can be exploited to divert cancer cells into becoming post-mitotic adipocytes, thus pre-
venting formation of metastases.

A cell’s ability to change its state and inducing receptors or their downstream tive regulator of adipogenesis, reduced
phenotype is a fundamental biological effectors. Other approaches aim at tar- the efficacy of the adipocyte-inducing
process necessary to develop and sustain geting the mesenchymal cell phenotype cocktail. A non-conical TGF-b-induced
organisms that was initially described as or blocking MET. These approaches all activation of Mek/Erk pathway was
early as 1908 (Lillie, 1908). Epithelial plas- essentially view epithelial plasticity as a identified as a negative regulator of
ticity, the ability to change phenotype in disadvantageous property of potentially induced adipogenesis in MTDECad and
response to biochemical, biomechanical, metastatic or invasive cells. Py2T-LT cells. Accordingly, inhibition of
or environmental cues, is immensely The study by Ishay-Ronen et al. in this Mek in combination with the rosiglita-
important considering that epithelial cells issue of Cancer Cell introduces a novel zone/BMP2 cocktail recovered adipogen-
are exposed to frequent stress events therapeutic exploitation of EMT (Ishay- esis in the presence of TGF-b. Indeed,
that require regenerative programs (Nieto, Ronen et al., 2019). In a window of plas- Mek inhibition enhanced induction of
2013). During embryogenesis, cells tran- ticity, created during EMT, the authors adipogenesis to such a degree that they
sition from an epithelial state to a mesen- drove metastatic breast cancer cells to determined addition of BMP2 was non-
chymal state (i.e., EMT) as well as from the differentiate into adipocytes, thus divert- essential.
mesenchymal state to an epithelial state ing the classical EMT process (Figure 1). In short-term murine in vivo models of
(i.e., MET). In the developed organism, A cocktail of rosiglitazone (an inhibitor of breast cancer, Ishay-Ronen et al. show
EMT is implicated in wound healing and peroxisome proliferator-activated recep- robust evidence that adipogenesis induc-
fibrosis. To ensure tissue integrity and tors) and BMP2 (part of the transforming tion via rosiglitazone together with Mek in-
maintenance of the homeostatic state, growth factor-beta [TGF-b] superfamily) hibition reduced invasiveness and limited
it is imperative that the EMT program was shown to influence mesenchymal, tumor mass. The cancer-derived adipo-
of epithelial cells in developed organs but not epithelial, murine mammary tumor cytes were predominantly localized to
is tightly controlled. The complexity of cells to undergo adipogenesis as indi- the border between tumor and normal
global cellular programs, including tran- cated by an enhanced expression of tissue, which is intriguing because that
scriptional, post-transcriptional, post- Cebpa (regulator of adipogenesis) and was hypothesized to be the region where
translational, and epigenetic, amplifies the enhanced formation of intracellular cancer cells undergo EMT (Kalluri and
the significance of EMT regulation. The lipid droplets. Functional adipocyte phe- Weinberg, 2009). Thus, the proposed
vast majority of cancers are of epithelial notypes were represented upon adipo- intervention forces cancer cells, which
origin, and epithelial plasticity can be genic differentiation of MTDECad tumor are transitioning through a vulnerable
enhanced during cancer progression; cells that underwent an irreversible EMT, state of plasticity, into becoming adipo-
indeed, these mechanisms are often as well as their positive control 3T3-L1 cytes and ultimately reduces potential
hijacked and rewired by tumor cells to cells, which are considered the gold metastatic burden. The authors reported
foster tumor growth, survival, and metas- standard for induced adipogenesis. Both an estimated >10-fold reduction in lung
tasis. Cancers that exhibit EMT pheno- cell types had comparable expression metastases compared to untreated con-
types are clinically challenging, as they patterns of adipocyte-specific markers trols in immune-deficient mice xeno-
are more prone to enhanced drug resis- (e.g., Cebpa, Pparg, Fabp4, and Adipoq), grafted with MDA-MB-321 LM cells
tance, metastasis, and poor overall pa- similar adipocytic metabolic signatures implanted into the mammary fat pads
tient survival (Nieto et al., 2016). and transcriptome profiles, as well as and treated with the adipogenesis-
Pharmacological targeting of EMT- loss of mesenchymal morphological phe- inducing drug combination of rosiglita-
related pathways is thought to be an notypes. The differentiation was irrevers- zone together with the FDA-approved
important breakthrough in cancer treat- ible, as removal of the cocktail did not Mek inhibitor trametinib. It remains to be
ment, especially considering that metas- result in the loss of the intracellular lipid seen whether the proposed intervention
tases account for most cancer-related droplets. Notably, the cancer cell-derived is beneficial in long-term tumor models
deaths (Davis et al., 2014). A number of adipocytes were found to be in post- or whether the immune system plays
therapeutic approaches that are currently mitotic cell-cycle arrest. The presence of any roles that will challenge this form of
being evaluated focus on inhibiting EMT- TGF-b, a strong EMT inducer and nega- differentiation therapy.

Cancer Cell 35, January 14, 2019 ª 2019 Elsevier Inc. 1

 Cancer Cell

Previews

otherwise deleterious cell state transi-

tion in the cancer progression, might
be exploited in solid tumors so as to
reduce a patient’s potential tumor burden
via forced adipogenesis of cancer cells.
This intriguing approach merits further
investigation.

DECLARATION OF INTERESTS

In addition to M.A.L.’s appointment at City of

Hope, he also is adjunct faculty at University of
Bergen, Norway and a visiting staff scientist at
Lawrence Berkley National Lab.

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Figure 1. Cartoon Representing Induced Non-Reversible Adipogenesis of Carcinoma Cells
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2 Cancer Cell 35, January 14, 2019