Oncogene (2018) 37:1519–1533
https://doi.org/10.1038/s41388-017-0062-6
ARTICLE
Lung fibroblasts promote metastatic colonization through
upregulation of stearoyl-CoA desaturase 1 in tumor cells
Guanghua Liu
1,2,3
●
Shi Feng
1,2,3
●
Lin Jia
1,2,3
●
Chunying Wang
1,2,3
●
Yan Fu
1,2,3
●
Yongzhang Luo
1,2,3
Received: 1 March 2017 / Revised: 30 October 2017 / Accepted: 7 November 2017 / Published online: 12 January 2018
© Macmillan Publishers Limited, part of Springer Nature 2018
Abstract
As a rate-limiting step in metastasis, metastatic colonization requires survival signals from supportive stroma. However, the
mechanisms driving this process are incompletely understood. Here, we showed that the proliferation of B16F10 cells was
promoted when cocultured with lung fibroblasts. Meanwhile, co-injection of B16F10 tumor cells with mouse lung
fibroblasts significantly increased lung metastasis. Based on GEO database, we identified stearoyl-CoA desaturase 1 (SCD1)
as a novel factor promoting metastatic colonization. Importantly, we found that fibroblast-secreted cathepsin B (CTSB)
induced the upregulation of SCD1 in B16F10 through Annexin A2 (ANXA2) and PI3K/Akt/mTOR pathway. The elevated
SCD1 induced a higher ratio of monounsaturated fatty acids to saturated fatty acids in B16F10 cells. The changes in fatty
acid composition contributed to tumor cell proliferation and metastatic colonization. Furthermore, targeting SCD1
effectively inhibited lung metastasis and prolonged the overall survival of mice. Meanwhile, the expression of SCD1 was
negatively correlated with disease-free survival in five types of cancer patients. Collectively, our study identifies SCD1 as a
critical modulator of tumor cell proliferation that is activated by cathepsin B, secreted by lung fibroblasts at the metastatic
niche. Our novel findings provide potential therapeutic targets to prevent tumor metastasis.
Introduction
As one of the most common malignant cancer types, the
incidence of melanoma is rising steadily in most Western
countries [1, 2]. Despite surgical resection that leads to a
good prognosis in the early stages of melanoma, the
majority of melanoma patients dies from secondary metas-
tasis, which has a very poor prognosis [2]. However, there
are not enough drugs targeting melanoma metastasis due to
a poor understanding of the mechanisms controlling this
clinically important process.
Metastasis is a highly inefficient process. Tumor cells
have to overcome many obstacles in the process of meta-
static cascade, among which organ colonization is regarded
as the most complicated and rate-limiting step, because
tumor cells need to face the challenges of lack of survival
signals and supportive stroma after the arrival at distant
organs [3]. Meanwhile, several studies have proved that the
interactions between tumor cells and stromal cells at distant
organs promote metastatic colonization. Malanchi and col-
leagues found that stromal fibroblasts contribute to meta-
static colonization through the expression of periostin,
which recruits Wnt ligands and increases Wnt signaling in
cancer stem cells [4]. Massagué’s group demonstrated that
the binding of macrophage to receptor VCAM-1 can induce
survival signals in breast cancer cells infiltrated in the lung
[5]. Wculek and Malanchi also found that neutrophil-
derived leukotrienes specifically support metastatic initia-
tion [6]. The data from Ahmed’s lab showed that adipocytes
accelerate ovarian cancer omental metastasis through the
activation of SIK2, which drives cancer cells survival and
fatty acid oxidation [7].
G. Liu and S. Feng contributed equally to this work.
* Yongzhang Luo
yluo@mail.tsinghua.edu.cn
1
The National Engineering Laboratory for Anti-Tumor Protein
Therapeutics, Tsinghua University, Beijing, China
2
Beijing Key Laboratory for Protein Therapeutics, Tsinghua
University, Beijing, China
3
Cancer Biology Laboratory, School of Life Sciences, Tsinghua
University, Beijing, China
Electronic supplementary material The online version of this article
(https://doi.org/10.1038/s41388-017-0062-6) contains supplementary
material, which is available to authorized users.
1234567890
@Phil_Robichaud
@deepthiw
@JoseServera