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Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis

Identifieur interne : 000729 ( Main/Exploration ); précédent : 000728; suivant : 000730

Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis

Auteurs : Zilong Yan [Japon] ; Kenoki Ohuchida [Japon] ; Shuang Fei [Japon] ; Biao Zheng [Japon, République populaire de Chine] ; Weiyu Guan [Japon] ; Haimin Feng [Japon] ; Shin Kibe [Japon] ; Yohei Ando [Japon] ; Kazuhiro Koikawa [Japon] ; Toshiya Abe [Japon] ; Chika Iwamoto [Japon] ; Koji Shindo [Japon] ; Taiki Moriyama [Japon] ; Kohei Nakata [Japon] ; Yoshihiro Miyasaka [Japon] ; Takao Ohtsuka [Japon] ; Kazuhiro Mizumoto [Japon] ; Makoto Hashizume [Japon] ; Masafumi Nakamura [Japon]

Source :

RBID : PMC:6537367

Descripteurs français

English descriptors

Abstract

Background

Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer–stromal interaction.

Methods

Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor.

Results

Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer–stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model.

Conclusions

These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis.

Electronic supplementary material

The online version of this article (10.1186/s13046-019-1226-8) contains supplementary material, which is available to authorized users.


Url:
DOI: 10.1186/s13046-019-1226-8
PubMed: 31133044
PubMed Central: 6537367


Affiliations:

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<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Advanced Medical Initiatives,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Fukuoka</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fei, Shuang" sort="Fei, Shuang" uniqKey="Fei S" first="Shuang" last="Fei">Shuang Fei</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Zheng, Biao" sort="Zheng, Biao" uniqKey="Zheng B" first="Biao" last="Zheng">Biao Zheng</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="Aff3">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 0472 9649</institution-id>
<institution-id institution-id-type="GRID">grid.263488.3</institution-id>
<institution>Department of General Surgery,</institution>
<institution>Shenzhen University General Hospital,</institution>
</institution-wrap>
Shenzhen, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Shenzhen</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Guan, Weiyu" sort="Guan, Weiyu" uniqKey="Guan W" first="Weiyu" last="Guan">Weiyu Guan</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Feng, Haimin" sort="Feng, Haimin" uniqKey="Feng H" first="Haimin" last="Feng">Haimin Feng</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Kibe, Shin" sort="Kibe, Shin" uniqKey="Kibe S" first="Shin" last="Kibe">Shin Kibe</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Ando, Yohei" sort="Ando, Yohei" uniqKey="Ando Y" first="Yohei" last="Ando">Yohei Ando</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Koikawa, Kazuhiro" sort="Koikawa, Kazuhiro" uniqKey="Koikawa K" first="Kazuhiro" last="Koikawa">Kazuhiro Koikawa</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Abe, Toshiya" sort="Abe, Toshiya" uniqKey="Abe T" first="Toshiya" last="Abe">Toshiya Abe</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Iwamoto, Chika" sort="Iwamoto, Chika" uniqKey="Iwamoto C" first="Chika" last="Iwamoto">Chika Iwamoto</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Advanced Medical Initiatives,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Fukuoka</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Shindo, Koji" sort="Shindo, Koji" uniqKey="Shindo K" first="Koji" last="Shindo">Koji Shindo</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Moriyama, Taiki" sort="Moriyama, Taiki" uniqKey="Moriyama T" first="Taiki" last="Moriyama">Taiki Moriyama</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Nakata, Kohei" sort="Nakata, Kohei" uniqKey="Nakata K" first="Kohei" last="Nakata">Kohei Nakata</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Miyasaka, Yoshihiro" sort="Miyasaka, Yoshihiro" uniqKey="Miyasaka Y" first="Yoshihiro" last="Miyasaka">Yoshihiro Miyasaka</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Ohtsuka, Takao" sort="Ohtsuka, Takao" uniqKey="Ohtsuka T" first="Takao" last="Ohtsuka">Takao Ohtsuka</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Mizumoto, Kazuhiro" sort="Mizumoto, Kazuhiro" uniqKey="Mizumoto K" first="Kazuhiro" last="Mizumoto">Kazuhiro Mizumoto</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0004 0404 8415</institution-id>
<institution-id institution-id-type="GRID">grid.411248.a</institution-id>
<institution>Cancer Center of Kyushu University Hospital,</institution>
</institution-wrap>
Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Fukuoka</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hashizume, Makoto" sort="Hashizume, Makoto" uniqKey="Hashizume M" first="Makoto" last="Hashizume">Makoto Hashizume</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Advanced Medical Initiatives,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Fukuoka</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Nakamura, Masafumi" sort="Nakamura, Masafumi" uniqKey="Nakamura M" first="Masafumi" last="Nakamura">Masafumi Nakamura</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2242 4849</institution-id>
<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
<institution>Department of Surgery and Oncology,</institution>
<institution>Graduate School of Medical Sciences, Kyushu University,</institution>
</institution-wrap>
3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>3-1-1 Maidashi, Fukuoka</wicri:regionArea>
<wicri:noRegion>Fukuoka</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Journal of Experimental & Clinical Cancer Research : CR</title>
<idno type="ISSN">0392-9078</idno>
<idno type="eISSN">1756-9966</idno>
<imprint>
<date when="2019">2019</date>
</imprint>
</series>
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<keywords scheme="KwdEn" xml:lang="en">
<term>Animals</term>
<term>Autophagy</term>
<term>Carcinoma, Pancreatic Ductal (drug therapy)</term>
<term>Carcinoma, Pancreatic Ductal (metabolism)</term>
<term>Cell Communication (drug effects)</term>
<term>Cell Line, Tumor</term>
<term>Cell Movement (drug effects)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Chloroquine (administration & dosage)</term>
<term>Chloroquine (pharmacology)</term>
<term>Drug Synergism</term>
<term>Epithelial-Mesenchymal Transition (drug effects)</term>
<term>Humans</term>
<term>Indazoles (administration & dosage)</term>
<term>Indazoles (pharmacology)</term>
<term>Mice</term>
<term>Mitogen-Activated Protein Kinase 1 (metabolism)</term>
<term>Mitogen-Activated Protein Kinase 3 (metabolism)</term>
<term>Neoplasm Metastasis</term>
<term>Pancreatic Neoplasms (drug therapy)</term>
<term>Pancreatic Neoplasms (metabolism)</term>
<term>Pancreatic Stellate Cells (metabolism)</term>
<term>Pancreatic Stellate Cells (pathology)</term>
<term>Phosphorylation (drug effects)</term>
<term>Piperazines (administration & dosage)</term>
<term>Piperazines (pharmacology)</term>
<term>Protein Kinase Inhibitors (administration & dosage)</term>
<term>Protein Kinase Inhibitors (pharmacology)</term>
<term>Stromal Cells (metabolism)</term>
<term>Stromal Cells (pathology)</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Animaux</term>
<term>Autophagie</term>
<term>Carcinome du canal pancréatique (métabolisme)</term>
<term>Carcinome du canal pancréatique (traitement médicamenteux)</term>
<term>Cellules stellaires pancréatiques (anatomopathologie)</term>
<term>Cellules stellaires pancréatiques (métabolisme)</term>
<term>Cellules stromales (anatomopathologie)</term>
<term>Cellules stromales (métabolisme)</term>
<term>Chloroquine (administration et posologie)</term>
<term>Chloroquine (pharmacologie)</term>
<term>Communication cellulaire ()</term>
<term>Humains</term>
<term>Indazoles (administration et posologie)</term>
<term>Indazoles (pharmacologie)</term>
<term>Inhibiteurs de protéines kinases (administration et posologie)</term>
<term>Inhibiteurs de protéines kinases (pharmacologie)</term>
<term>Lignée cellulaire tumorale</term>
<term>Mitogen-Activated Protein Kinase 1 (métabolisme)</term>
<term>Mitogen-Activated Protein Kinase 3 (métabolisme)</term>
<term>Mouvement cellulaire ()</term>
<term>Métastase tumorale</term>
<term>Phosphorylation ()</term>
<term>Pipérazines (administration et posologie)</term>
<term>Pipérazines (pharmacologie)</term>
<term>Prolifération cellulaire ()</term>
<term>Souris</term>
<term>Synergie des médicaments</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
<term>Transition épithélio-mésenchymateuse ()</term>
<term>Tumeurs du pancréas (métabolisme)</term>
<term>Tumeurs du pancréas (traitement médicamenteux)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en">
<term>Chloroquine</term>
<term>Indazoles</term>
<term>Piperazines</term>
<term>Protein Kinase Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr">
<term>Chloroquine</term>
<term>Indazoles</term>
<term>Inhibiteurs de protéines kinases</term>
<term>Pipérazines</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Cellules stellaires pancréatiques</term>
<term>Cellules stromales</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Cell Communication</term>
<term>Cell Movement</term>
<term>Cell Proliferation</term>
<term>Epithelial-Mesenchymal Transition</term>
<term>Phosphorylation</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Carcinoma, Pancreatic Ductal</term>
<term>Pancreatic Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Carcinoma, Pancreatic Ductal</term>
<term>Mitogen-Activated Protein Kinase 1</term>
<term>Mitogen-Activated Protein Kinase 3</term>
<term>Pancreatic Neoplasms</term>
<term>Pancreatic Stellate Cells</term>
<term>Stromal Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Carcinome du canal pancréatique</term>
<term>Cellules stellaires pancréatiques</term>
<term>Cellules stromales</term>
<term>Mitogen-Activated Protein Kinase 1</term>
<term>Mitogen-Activated Protein Kinase 3</term>
<term>Tumeurs du pancréas</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Pancreatic Stellate Cells</term>
<term>Stromal Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Chloroquine</term>
<term>Indazoles</term>
<term>Inhibiteurs de protéines kinases</term>
<term>Pipérazines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Chloroquine</term>
<term>Indazoles</term>
<term>Piperazines</term>
<term>Protein Kinase Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Carcinome du canal pancréatique</term>
<term>Tumeurs du pancréas</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Autophagy</term>
<term>Cell Line, Tumor</term>
<term>Drug Synergism</term>
<term>Humans</term>
<term>Mice</term>
<term>Neoplasm Metastasis</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Autophagie</term>
<term>Communication cellulaire</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Mouvement cellulaire</term>
<term>Métastase tumorale</term>
<term>Phosphorylation</term>
<term>Prolifération cellulaire</term>
<term>Souris</term>
<term>Synergie des médicaments</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
<term>Transition épithélio-mésenchymateuse</term>
</keywords>
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<front>
<div type="abstract" xml:lang="en">
<sec>
<title>Background</title>
<p id="Par1">Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of
<italic>KRAS</italic>
-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer–stromal interaction.</p>
</sec>
<sec>
<title>Methods</title>
<p id="Par2">Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor.</p>
</sec>
<sec>
<title>Results</title>
<p id="Par3">Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer–stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model.</p>
</sec>
<sec>
<title>Conclusions</title>
<p id="Par4">These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis.</p>
</sec>
<sec>
<title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s13046-019-1226-8) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
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<name sortKey="Abe, Toshiya" sort="Abe, Toshiya" uniqKey="Abe T" first="Toshiya" last="Abe">Toshiya Abe</name>
<name sortKey="Ando, Yohei" sort="Ando, Yohei" uniqKey="Ando Y" first="Yohei" last="Ando">Yohei Ando</name>
<name sortKey="Fei, Shuang" sort="Fei, Shuang" uniqKey="Fei S" first="Shuang" last="Fei">Shuang Fei</name>
<name sortKey="Feng, Haimin" sort="Feng, Haimin" uniqKey="Feng H" first="Haimin" last="Feng">Haimin Feng</name>
<name sortKey="Guan, Weiyu" sort="Guan, Weiyu" uniqKey="Guan W" first="Weiyu" last="Guan">Weiyu Guan</name>
<name sortKey="Hashizume, Makoto" sort="Hashizume, Makoto" uniqKey="Hashizume M" first="Makoto" last="Hashizume">Makoto Hashizume</name>
<name sortKey="Iwamoto, Chika" sort="Iwamoto, Chika" uniqKey="Iwamoto C" first="Chika" last="Iwamoto">Chika Iwamoto</name>
<name sortKey="Kibe, Shin" sort="Kibe, Shin" uniqKey="Kibe S" first="Shin" last="Kibe">Shin Kibe</name>
<name sortKey="Koikawa, Kazuhiro" sort="Koikawa, Kazuhiro" uniqKey="Koikawa K" first="Kazuhiro" last="Koikawa">Kazuhiro Koikawa</name>
<name sortKey="Miyasaka, Yoshihiro" sort="Miyasaka, Yoshihiro" uniqKey="Miyasaka Y" first="Yoshihiro" last="Miyasaka">Yoshihiro Miyasaka</name>
<name sortKey="Mizumoto, Kazuhiro" sort="Mizumoto, Kazuhiro" uniqKey="Mizumoto K" first="Kazuhiro" last="Mizumoto">Kazuhiro Mizumoto</name>
<name sortKey="Moriyama, Taiki" sort="Moriyama, Taiki" uniqKey="Moriyama T" first="Taiki" last="Moriyama">Taiki Moriyama</name>
<name sortKey="Nakamura, Masafumi" sort="Nakamura, Masafumi" uniqKey="Nakamura M" first="Masafumi" last="Nakamura">Masafumi Nakamura</name>
<name sortKey="Nakata, Kohei" sort="Nakata, Kohei" uniqKey="Nakata K" first="Kohei" last="Nakata">Kohei Nakata</name>
<name sortKey="Ohtsuka, Takao" sort="Ohtsuka, Takao" uniqKey="Ohtsuka T" first="Takao" last="Ohtsuka">Takao Ohtsuka</name>
<name sortKey="Ohuchida, Kenoki" sort="Ohuchida, Kenoki" uniqKey="Ohuchida K" first="Kenoki" last="Ohuchida">Kenoki Ohuchida</name>
<name sortKey="Ohuchida, Kenoki" sort="Ohuchida, Kenoki" uniqKey="Ohuchida K" first="Kenoki" last="Ohuchida">Kenoki Ohuchida</name>
<name sortKey="Shindo, Koji" sort="Shindo, Koji" uniqKey="Shindo K" first="Koji" last="Shindo">Koji Shindo</name>
<name sortKey="Zheng, Biao" sort="Zheng, Biao" uniqKey="Zheng B" first="Biao" last="Zheng">Biao Zheng</name>
</country>
<country name="République populaire de Chine">
<noRegion>
<name sortKey="Zheng, Biao" sort="Zheng, Biao" uniqKey="Zheng B" first="Biao" last="Zheng">Biao Zheng</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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