Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis
Identifieur interne : 000653 ( Ncbi/Curation ); précédent : 000652; suivant : 000654Inhibition 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 :
- Journal of Experimental & Clinical Cancer Research : CR [ 0392-9078 ] ; 2019.
Descripteurs français
- KwdFr :
- Animaux, Autophagie, Carcinome du canal pancréatique (métabolisme), Carcinome du canal pancréatique (traitement médicamenteux), Cellules stellaires pancréatiques (anatomopathologie), Cellules stellaires pancréatiques (métabolisme), Cellules stromales (anatomopathologie), Cellules stromales (métabolisme), Chloroquine (administration et posologie), Chloroquine (pharmacologie), Communication cellulaire (), Humains, Indazoles (administration et posologie), Indazoles (pharmacologie), Inhibiteurs de protéines kinases (administration et posologie), Inhibiteurs de protéines kinases (pharmacologie), Lignée cellulaire tumorale, Mitogen-Activated Protein Kinase 1 (métabolisme), Mitogen-Activated Protein Kinase 3 (métabolisme), Mouvement cellulaire (), Métastase tumorale, Phosphorylation (), Pipérazines (administration et posologie), Pipérazines (pharmacologie), Prolifération cellulaire (), Souris, Synergie des médicaments, Tests d'activité antitumorale sur modèle de xénogreffe, Transition épithélio-mésenchymateuse (), Tumeurs du pancréas (métabolisme), Tumeurs du pancréas (traitement médicamenteux).
- MESH :
- administration et posologie : Chloroquine, Indazoles, Inhibiteurs de protéines kinases, Pipérazines.
- anatomopathologie : Cellules stellaires pancréatiques, Cellules stromales.
- métabolisme : Carcinome du canal pancréatique, Cellules stellaires pancréatiques, Cellules stromales, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Tumeurs du pancréas.
- pharmacologie : Chloroquine, Indazoles, Inhibiteurs de protéines kinases, Pipérazines.
- traitement médicamenteux : Carcinome du canal pancréatique, Tumeurs du pancréas.
- Animaux, Autophagie, Communication cellulaire, Humains, Lignée cellulaire tumorale, Mouvement cellulaire, Métastase tumorale, Phosphorylation, Prolifération cellulaire, Souris, Synergie des médicaments, Tests d'activité antitumorale sur modèle de xénogreffe, Transition épithélio-mésenchymateuse.
English descriptors
- KwdEn :
- Animals, Autophagy, Carcinoma, Pancreatic Ductal (drug therapy), Carcinoma, Pancreatic Ductal (metabolism), Cell Communication (drug effects), Cell Line, Tumor, Cell Movement (drug effects), Cell Proliferation (drug effects), Chloroquine (administration & dosage), Chloroquine (pharmacology), Drug Synergism, Epithelial-Mesenchymal Transition (drug effects), Humans, Indazoles (administration & dosage), Indazoles (pharmacology), Mice, Mitogen-Activated Protein Kinase 1 (metabolism), Mitogen-Activated Protein Kinase 3 (metabolism), Neoplasm Metastasis, Pancreatic Neoplasms (drug therapy), Pancreatic Neoplasms (metabolism), Pancreatic Stellate Cells (metabolism), Pancreatic Stellate Cells (pathology), Phosphorylation (drug effects), Piperazines (administration & dosage), Piperazines (pharmacology), Protein Kinase Inhibitors (administration & dosage), Protein Kinase Inhibitors (pharmacology), Stromal Cells (metabolism), Stromal Cells (pathology), Xenograft Model Antitumor Assays.
- MESH :
- chemical , administration & dosage : Chloroquine, Indazoles, Piperazines, Protein Kinase Inhibitors.
- drug effects : Cell Communication, Cell Movement, Cell Proliferation, Epithelial-Mesenchymal Transition, Phosphorylation.
- drug therapy : Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms.
- metabolism : Carcinoma, Pancreatic Ductal, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Pancreatic Neoplasms, Pancreatic Stellate Cells, Stromal Cells.
- pathology : Pancreatic Stellate Cells, Stromal Cells.
- chemical , pharmacology : Chloroquine, Indazoles, Piperazines, Protein Kinase Inhibitors.
- Animals, Autophagy, Cell Line, Tumor, Drug Synergism, Humans, Mice, Neoplasm Metastasis, Xenograft Model Antitumor Assays.
Abstract
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
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.
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.
These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis.
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
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PMC:6537367Le document en format XML
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<author><name sortKey="Ohtsuka, Takao" sort="Ohtsuka, Takao" uniqKey="Ohtsuka T" first="Takao" last="Ohtsuka">Takao Ohtsuka</name>
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<author><name sortKey="Mizumoto, Kazuhiro" sort="Mizumoto, Kazuhiro" uniqKey="Mizumoto K" first="Kazuhiro" last="Mizumoto">Kazuhiro Mizumoto</name>
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<author><name sortKey="Hashizume, Makoto" sort="Hashizume, Makoto" uniqKey="Hashizume M" first="Makoto" last="Hashizume">Makoto Hashizume</name>
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Fukuoka, Japan</nlm:aff>
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<author><name sortKey="Nakamura, Masafumi" sort="Nakamura, Masafumi" uniqKey="Nakamura M" first="Masafumi" last="Nakamura">Masafumi Nakamura</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis</title>
<author><name sortKey="Yan, Zilong" sort="Yan, Zilong" uniqKey="Yan Z" first="Zilong" last="Yan">Zilong Yan</name>
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<institution>Department of Surgery and Oncology,</institution>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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</author>
<author><name sortKey="Ohuchida, Kenoki" sort="Ohuchida, Kenoki" uniqKey="Ohuchida K" first="Kenoki" last="Ohuchida">Kenoki Ohuchida</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
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<institution>Department of Advanced Medical Initiatives,</institution>
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Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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</author>
<author><name sortKey="Fei, Shuang" sort="Fei, Shuang" uniqKey="Fei S" first="Shuang" last="Fei">Shuang Fei</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
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</author>
<author><name sortKey="Zheng, Biao" sort="Zheng, Biao" uniqKey="Zheng B" first="Biao" last="Zheng">Biao Zheng</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<institution>Department of General Surgery,</institution>
<institution>Shenzhen University General Hospital,</institution>
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Shenzhen, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
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<author><name sortKey="Guan, Weiyu" sort="Guan, Weiyu" uniqKey="Guan W" first="Weiyu" last="Guan">Weiyu Guan</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
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</author>
<author><name sortKey="Feng, Haimin" sort="Feng, Haimin" uniqKey="Feng H" first="Haimin" last="Feng">Haimin Feng</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<author><name sortKey="Kibe, Shin" sort="Kibe, Shin" uniqKey="Kibe S" first="Shin" last="Kibe">Shin Kibe</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<author><name sortKey="Ando, Yohei" sort="Ando, Yohei" uniqKey="Ando Y" first="Yohei" last="Ando">Yohei Ando</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<author><name sortKey="Koikawa, Kazuhiro" sort="Koikawa, Kazuhiro" uniqKey="Koikawa K" first="Kazuhiro" last="Koikawa">Kazuhiro Koikawa</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
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<author><name sortKey="Abe, Toshiya" sort="Abe, Toshiya" uniqKey="Abe T" first="Toshiya" last="Abe">Toshiya Abe</name>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<author><name sortKey="Iwamoto, Chika" sort="Iwamoto, Chika" uniqKey="Iwamoto C" first="Chika" last="Iwamoto">Chika Iwamoto</name>
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Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Fukuoka</wicri:regionArea>
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<author><name sortKey="Shindo, Koji" sort="Shindo, Koji" uniqKey="Shindo K" first="Koji" last="Shindo">Koji Shindo</name>
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<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<author><name sortKey="Moriyama, Taiki" sort="Moriyama, Taiki" uniqKey="Moriyama T" first="Taiki" last="Moriyama">Taiki Moriyama</name>
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<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
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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>
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<author><name sortKey="Nakata, Kohei" sort="Nakata, Kohei" uniqKey="Nakata K" first="Kohei" last="Nakata">Kohei Nakata</name>
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<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
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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>
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</author>
<author><name sortKey="Miyasaka, Yoshihiro" sort="Miyasaka, Yoshihiro" uniqKey="Miyasaka Y" first="Yoshihiro" last="Miyasaka">Yoshihiro Miyasaka</name>
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<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<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>
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<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<wicri:noRegion>Fukuoka</wicri:noRegion>
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</author>
<author><name sortKey="Mizumoto, Kazuhiro" sort="Mizumoto, Kazuhiro" uniqKey="Mizumoto K" first="Kazuhiro" last="Mizumoto">Kazuhiro Mizumoto</name>
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Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<author><name sortKey="Hashizume, Makoto" sort="Hashizume, Makoto" uniqKey="Hashizume M" first="Makoto" last="Hashizume">Makoto Hashizume</name>
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Fukuoka, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
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<author><name sortKey="Nakamura, Masafumi" sort="Nakamura, Masafumi" uniqKey="Nakamura M" first="Masafumi" last="Nakamura">Masafumi Nakamura</name>
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<institution-id institution-id-type="GRID">grid.177174.3</institution-id>
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3-1-1 Maidashi, Fukuoka, 812-8582 Japan</nlm:aff>
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<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>
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<profileDesc><textClass><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>
</textClass>
</profileDesc>
</teiHeader>
<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>
</front>
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