Articles
https://doi.org/10.1038/s41591-018-0054-2
1
Institute for Cancer Genetics, Columbia University, New York, NY, USA.
2
Department of Preventive Medicine, Northwestern University Feinberg School
of Medicine, Chicago, IL, USA.
3
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska
Medical Center, Omaha, NE, USA.
4
Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
Division
of Neuropathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New
York, NY, USA.
6
Mailman School of Public Health, Columbia University, New York, NY, USA.
7
Department of Pathology and Laboratory Medicine, Weill
Cornell Medicine, New York, NY, USA.
8
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
9
Food
Science and Human Nutrition Department, University of Florida, Gainesville, FL, USA.
10
Deutsches Rheuma-Forschungszentrum Berlin, Osteoimmunology,
Berlin, Germany.
11
Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
12
Herbert Irving
Comprehensive Cancer Center, Columbia University, New York, NY, USA.
13
These authors contributed equally: Gang Wang, Anup K. Biswas, Wanchao Ma.
*e-mail: sa3141@cumc.columbia.edu
T
he vast majority of cancer-related deaths that occur are due
to metastasis
1,2
. Lethality from metastasis can be attributed to
two distinct factors. First, the invasion and growth of meta
-
static cancer cells within different organs can disrupt their normal
physiological functions. Second, metastatic tumors release soluble
proteins, exosomes and metabolites
3–5
that can systemically affect
organs that are otherwise free of cancer. For instance, cancer cells
rarely metastasize to skeletal muscle, but tumor-secreted factors
induce extensive muscle wasting
3
, resulting in a syndrome known
as cachexia
6,7
. Patients with cancer cachexia often become too weak
to tolerate standard doses of anticancer therapies, and those with
wasting of diaphragm and cardiac muscles often die prematurely
because of respiratory and cardiac failure
6,8
. Notably, cachexia short-
ens the survival of patients with cancer, and there are no approved
drugs that can effectively alleviate this condition
9
.
A characteristic feature of cancer cachexia is a reduction in
muscle size, also known as muscle atrophy. This is a process char
-
acterized by marked deterioration of cellular organelles, cytoplasm
and proteins in muscles
10,11
. Indeed, enhanced breakdown of muscle
proteins, often accompanied by decreased synthesis, contributes
to the altered muscle homeostasis and muscle mass loss in cancer
cachexia
6
. Although cachexia is a key indicator of poor prognosis
in patients with cancer, the mechanisms underlying muscle wasting
remain poorly understood.
Cachexia is predominantly observed in patients with advanced
cancer and metastasis
3,12,13
. To identify new potential mediators
and drivers of metastatic cancer–induced cachexia, we analyzed
five independent metastatic models of colon, breast and lung can
-
cer that gradually develop cachexia during metastatic progression.
These analyses identified a zinc transporter, solute carrier family 39,
member 14 (Slc39a14, also known as Zip14)
14
, that was significantly
upregulated in the cachectic muscles from metastatic cancer mouse
models and patients.
Zinc is essential for normal growth and immune function as
well as the activity of many transcription factors and enzymes
15,16
.
Interestingly, excess zinc accumulation has been observed in cachec
-
tic muscles in animal models and in patients
17,18
, but the mechanism
driving this accumulation and the consequence of muscle zinc over
-
load during cancer metastasis has not been studied. By manipulat-
ing Zip14 expression in vivo using mouse models of metastatic
cancer, we demonstrate that ZIP14-mediated zinc influx in muscle
cells is critical for the development of cancer-induced cachexia. Our
findings uncover a new role for ZIP14 in promoting muscle atrophy
and potentially blocking muscle regeneration in metastatic cancer.
Results
Development of cachexia in models of metastatic cancer. To
investigate the mechanisms that drive muscle wasting during
the advanced stages of cancer
7,12
, we performed allografts using
4T1 cells, a mouse metastatic breast cancer cell line, and C26m2
cells, a metastatic subline of C26 mouse colon cancer cells that we
generated (Fig. 1a and Supplementary Fig. 1a,b) through in vivo
Metastatic cancers promote cachexia through
ZIP14 upregulation in skeletal muscle
Gang Wang
1,13
, Anup K. Biswas
1,13
, Wanchao Ma
1,13
, Manoj Kandpal
2
, Courtney Coker
1
,
Paul M. Grandgenett
3
, Michael A. Hollingsworth
3
, Rinku Jain
4
, Kurenai Tanji
5
, Sara López-Pintado
6
,
Alain Borczuk
7
, Doreen Hebert
8
, Supak Jenkitkasemwong
9
, Shintaro Hojyo
10
, Ramana V. Davuluri
2
,
Mitchell D. Knutson
9
, Toshiyuki Fukada
11
and Swarnali Acharyya
1,8,12
*
Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is
associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly
understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-
induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced
by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle
atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expres-
sion of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differen-
tiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc
homeostasis in metastatic cancer–induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.
NATURE MEDICINE | VOL 24 | JUNE 2018 | 770–781 | www.nature.com/naturemedicine
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