Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing b1 integrin, enhancing drug resistance

Tomoyuki Uchihara; Keisuke Miyake; Atsuko Yonemura; Yoshihiro Komohara; Rumi Itoyama; Mayu Koiwa; Tadahito Yasuda; Kota Arima; Kazuto Harada; Kojiro Eto; Hiromitsu Hayashi; Masaaki Iwatsuki; Shiro Iwagami; Yoshifumi Baba; Naoya Yoshida; Masakazu Yashiro; Mari Masuda; Jaffer A. Ajani; Patrick Tan; Hideo Baba; Takatsugu Ishimoto

doi:10.1158/0008-5472.CAN-19-3803

Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing b1 integrin, enhancing drug resistance

Tomoyuki Uchihara, Keisuke Miyake, Atsuko Yonemura, Yoshihiro Komohara, Rumi Itoyama, Mayu Koiwa, Tadahito Yasuda, Kota Arima, Kazuto Harada, Kojiro Eto, Hiromitsu Hayashi, Masaaki Iwatsuki, Shiro Iwagami, Yoshifumi Baba, Naoya Yoshida, Masakazu Yashiro, Mari Masuda, Jaffer A. Ajani, Patrick Tan, Hideo BabaTakatsugu Ishimoto

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

Abstract

Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of b1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.

Original language	English (US)
Pages (from-to)	3222-3235
Number of pages	14
Journal	Cancer Research
Volume	80
Issue number	16
DOIs	https://doi.org/10.1158/0008-5472.CAN-19-3803
State	Published - Aug 15 2020

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/0008-5472.CAN-19-3803

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Uchihara, T., Miyake, K., Yonemura, A., Komohara, Y., Itoyama, R., Koiwa, M., Yasuda, T., Arima, K., Harada, K., Eto, K., Hayashi, H., Iwatsuki, M., Iwagami, S., Baba, Y., Yoshida, N., Yashiro, M., Masuda, M., Ajani, J. A., Tan, P., ... Ishimoto, T. (2020). Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing b1 integrin, enhancing drug resistance. Cancer Research, 80(16), 3222-3235. https://doi.org/10.1158/0008-5472.CAN-19-3803

Uchihara, T, Miyake, K, Yonemura, A, Komohara, Y, Itoyama, R, Koiwa, M, Yasuda, T, Arima, K, Harada, K, Eto, K, Hayashi, H, Iwatsuki, M, Iwagami, S, Baba, Y, Yoshida, N, Yashiro, M, Masuda, M, Ajani, JA, Tan, P, Baba, H & Ishimoto, T 2020, 'Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing b1 integrin, enhancing drug resistance', Cancer Research, vol. 80, no. 16, pp. 3222-3235. https://doi.org/10.1158/0008-5472.CAN-19-3803

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title = "Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing b1 integrin, enhancing drug resistance",

abstract = "Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of b1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.",

author = "Tomoyuki Uchihara and Keisuke Miyake and Atsuko Yonemura and Yoshihiro Komohara and Rumi Itoyama and Mayu Koiwa and Tadahito Yasuda and Kota Arima and Kazuto Harada and Kojiro Eto and Hiromitsu Hayashi and Masaaki Iwatsuki and Shiro Iwagami and Yoshifumi Baba and Naoya Yoshida and Masakazu Yashiro and Mari Masuda and Ajani, {Jaffer A.} and Patrick Tan and Hideo Baba and Takatsugu Ishimoto",

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month = aug,

day = "15",

doi = "10.1158/0008-5472.CAN-19-3803",

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T1 - Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing b1 integrin, enhancing drug resistance

AU - Uchihara, Tomoyuki

AU - Miyake, Keisuke

AU - Yonemura, Atsuko

AU - Komohara, Yoshihiro

AU - Itoyama, Rumi

AU - Koiwa, Mayu

AU - Yasuda, Tadahito

AU - Arima, Kota

AU - Harada, Kazuto

AU - Eto, Kojiro

AU - Hayashi, Hiromitsu

AU - Iwatsuki, Masaaki

AU - Iwagami, Shiro

AU - Baba, Yoshifumi

AU - Yoshida, Naoya

AU - Yashiro, Masakazu

AU - Masuda, Mari

AU - Ajani, Jaffer A.

AU - Tan, Patrick

AU - Baba, Hideo

AU - Ishimoto, Takatsugu

PY - 2020/8/15

Y1 - 2020/8/15

N2 - Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of b1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.

AB - Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of b1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.

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Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing b1 integrin, enhancing drug resistance

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