TY - JOUR
T1 - Uncovering Tumor-Promoting Roles of Activin A in Pancreatic Ductal Adenocarcinoma
AU - Yu, Seok Yeong
AU - Luan, Yi
AU - Tang, Siyuan
AU - Abazarikia, Amirhossein
AU - Dong, Rosemary
AU - Caffrey, Thomas C.
AU - Hollingsworth, Michael A.
AU - Oupicky, David
AU - Kim, So Youn
N1 - Funding Information:
This work was supported by startup funds from UNMC (S.Y.K.), Nebraska Collaboration Initiative NRI2132270010 (S.Y.K.), NIGMS COBRE (P30 GM127200) (S.Y.K. and D.O.), and R01 CA235863 (D.O.). The Small Animal Ultrasound Core at UNMC was supported in part by funding from the Nebraska Center for Nanomedicine COBRE grant (5P30 GM127200‐03). The authors thank Dr. Brian Hackfort for help with the ultrasound tumor imaging in orthotopic mice.
Publisher Copyright:
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
PY - 2023/6/2
Y1 - 2023/6/2
N2 - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high incidence rates of metastasis and cachexia. High circulating activin A, a homodimer of inhibin βA subunits that are encoded by INHBA gene, predicts poor survival among PDAC patients. However, it still raises the question of whether activin A suppression renders favorable PDAC outcomes. Here, the authors demonstrate that activin A is abundantly detected in tumor and stromal cells on PDAC tissue microarray and mouse PDAC sections. In orthotopic male mice, activin A suppression, which is acquired by tumor-targeted Inhba siRNA using cholesterol-modified polymeric nanoparticles, retards tumor growth/metastasis and cachexia and improves survival when compared to scramble siRNA-treated group. Histologically, activin A suppression coincides with decreased expression of proliferation marker Ki67 but increased accumulation of α-SMAhigh fibroblasts and cytotoxic T cells in the tumors. In vitro data demonstrate that activin A promotes KPC cell proliferation and induces the downregulation of α-SMA and upregulation of IL-6 in pancreatic stellate cells (PSC) in the SMAD3-dependent mechanism. Moreover, conditioned media from activin A-stimulated PSC promoted KPC cell growth. Collectively, our data provide a mechanistic basis for tumor-promoting roles of activin A and support therapeutic potentials of tumor activin A suppression for PDAC.
AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high incidence rates of metastasis and cachexia. High circulating activin A, a homodimer of inhibin βA subunits that are encoded by INHBA gene, predicts poor survival among PDAC patients. However, it still raises the question of whether activin A suppression renders favorable PDAC outcomes. Here, the authors demonstrate that activin A is abundantly detected in tumor and stromal cells on PDAC tissue microarray and mouse PDAC sections. In orthotopic male mice, activin A suppression, which is acquired by tumor-targeted Inhba siRNA using cholesterol-modified polymeric nanoparticles, retards tumor growth/metastasis and cachexia and improves survival when compared to scramble siRNA-treated group. Histologically, activin A suppression coincides with decreased expression of proliferation marker Ki67 but increased accumulation of α-SMAhigh fibroblasts and cytotoxic T cells in the tumors. In vitro data demonstrate that activin A promotes KPC cell proliferation and induces the downregulation of α-SMA and upregulation of IL-6 in pancreatic stellate cells (PSC) in the SMAD3-dependent mechanism. Moreover, conditioned media from activin A-stimulated PSC promoted KPC cell growth. Collectively, our data provide a mechanistic basis for tumor-promoting roles of activin A and support therapeutic potentials of tumor activin A suppression for PDAC.
KW - activin A
KW - cancer-associated fibroblasts
KW - cholesterol-modified polymeric nanoparticle
KW - orthotopic mice
KW - pancreatic ductal adenocarcinoma
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U2 - 10.1002/advs.202207010
DO - 10.1002/advs.202207010
M3 - Article
C2 - 37083240
AN - SCOPUS:85153531845
SN - 2198-3844
VL - 10
JO - Advanced Science
JF - Advanced Science
IS - 16
M1 - 2207010
ER -