Article
Gastroenterology & Hepatology
Carolina J. Garcia Garcia, Yanqing Huang, Natividad R. Fuentes, Madeleine C. Turner, Maria E. Monberg, Daniel Lin, Nicholas D. Nguyen, Tara N. Fujimoto, Jun Zhao, Jaewon J. Lee, Vincent Bernard, Meifang Yu, Abagail M. Delahoussaye, Iancarlos Jimenez Sacarello, Emily G. Caggiano, Jae L. Phan, Amit Deorukhkar, Jessica M. Molkentine, Dieter Saur, Anirban Maitra, Cullen M. Taniguchi
Summary: In pancreatic ductal adenocarcinoma, stromal HIF2 appears to play a crucial role and represents a druggable target to alleviate tumor microenvironment immunosuppression and enhance immune responses.
Article
Cell Biology
Blaz Lupse, Karthika Annamalai, Hazem Ibrahim, Supreet Kaur, Shirin Geravandi, Bhavishya Sarma, Anasua Pal, Sushil Awal, Arundhati Joshi, Sahar Rafizadeh, Murali Krishna Madduri, Mona Khazaei, Huan Liu, Ting Yuan, Wei He, Kanaka Durga Devi Gorrepati, Zahra Azizi, Qi Qi, Keqiang Ye, Jose Oberholzer, Kathrin Maedler, Amin Ardestani
Summary: The upregulation of PHLPP1 and PHLPP2 in diabetes leads to pancreatic beta-cell failure, primarily through the regulation of mTORC1 activation levels and subsequently influencing beta-cell survival and function, resulting in beta-cell apoptosis. Genetic inhibition of PHLPP markedly improves beta-cell survival and function in experimental models of diabetes.
Article
Biochemistry & Molecular Biology
Joy M. Davis, Binglu Cheng, Madeline M. Drake, Qiang Yu, Baibing Yang, Jing Li, Chunhui Liu, Mamoun Younes, Xiurong Zhao, Jennifer M. Bailey, Qiang Shen, Tien C. Ko, Yanna Cao
Summary: Chronic pancreatitis is a major risk factor for pancreatic ductal adenocarcinoma, but the mechanism by which CP promotes pancreatic oncogenesis remains unclear. Our study found that GREM1 expression by fibroblasts correlates with the development of PDAC and is associated with macrophages in the pancreatic tumor microenvironment. Gremlin 1 may play a role in promoting PDAC development and influencing macrophage phenotype.
Article
Oncology
Akane Ueki, Masayuki Komura, Akira Koshino, Chengbo Wang, Kazuhiro Nagao, Mai Homochi, Yuki Tsukada, Masahide Ebi, Naotaka Ogasawara, Toyonori Tsuzuki, Kenji Kasai, Kunio Kasugai, Satoru Takahashi, Shingo Inaguma
Summary: This study found that 44% of colorectal cancer (CRC) cases exhibited periostin (POSTN) expression in cancer-associated fibroblasts (CAFs). POSTN expression in CRC cells was almost undetectable. Patients with POSTN-positive CRC had significantly worse 5-year survival rates and increased peritoneal and distant organ metastasis. POSTN was also associated with p53 loss in CRC cells. POSTN enhanced the migration of CRC cells and fibroblasts through FAK and AKT or STAT3 activation. Stromal POSTN accelerated metastasis and activated migration of tumor and stromal cells.
Article
Endocrinology & Metabolism
Byung-Jun Sung, Sung-Bin Lim, Won-Mo Yang, Jae Hyeon Kim, Rohit N. Kulkarni, Young-Bum Kim, Moon-Kyu Lee
Summary: This study reveals the essential role of ROCK1 in regulating glucose-stimulated insulin secretion and glucose homeostasis in pancreatic β-cells. ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling, and its deficiency impairs insulin secretion and glucose tolerance.
MOLECULAR METABOLISM
(2022)
Article
Oncology
Hangqi Liu, Hui Zhang, Xiaoqian Liu, Wenting Guo, Qiaofei Liu, Longyun Chen, Junyi Pang, Xiaoding Liu, Ruiyu Li, Huanwen Wu, Menghua Dai, Zhiyong Liang
Summary: Pancreatic stellate cells (PSCs) play a critical role in the metabolism and progression of pancreatic ductal adeno-carcinoma (PDAC). This study identified the Wnt/beta-catenin/TCF7/GS-mediated growth-promoting effect of PSCs and provided new insights into stromal glutamine (Gln) metabolism, which may offer novel therapeutic strategies for PDAC.
Article
Oncology
Varintra E. Lander, Jad I. Belle, Natalie L. Kingston, John M. Herndon, Graham D. Hogg, Xiuting Liu, Liang- Kang, Brett L. Knolhoff, Savannah J. Bogner, John M. Baer, Chong Zuo, Nicholas C. Borcherding, Daniel P. Lander, Cedric Mpoy, Jalen Scott, Michael Zahner, Buck E. Rogers, Julie K. Schwarz, Hyun Kim, David G. DeNardo
Summary: The effects of radiotherapy on tumor immunity in pancreatic ductal adenocarcinoma are not well understood. In this study, FAK inhibition was found to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy in combination with radiotherapy.
Article
Medicine, General & Internal
Xiuhui Shi, Min Wang, Yuqing Zhang, Xingjun Guo, Mingyang Liu, Zhijun Zhou, Yan Zhao, Ruizhi He, Yang Gao, Yuhui Liu, Shutao Pan, Min Zhou, Chunle Zhao, Taoyuan Yin, Xu Li, Hebin Wang, Jingxuan Yang, Feng Zhu, Min Li, Renyi Qin
Summary: High expression levels of alpha-SMA and hypoxia markers are associated with poor prognosis in pancreatic cancer patients. Mechanistically, hypoxia induces HGF expression and secretion in PSC via HIF-1 alpha, which then activates Met and suppresses pancreatic cancer cell sensitivity to EGFR inhibitors. The combination of EGFR inhibitor and Met inhibitor shows promise for pancreatic cancer treatment based on the demonstrated signaling axis between PSC and cancer cells.
Article
Oncology
Yuchen Zhang, Michael B. Ware, Mohammad Y. Zaidi, Amanda N. Ruggieri, Brian M. Olson, Hannah Komar, Matthew R. Farren, Ganji Purnachandra Nagaraju, Chao Zhang, Zhengjia Chen, Juan M. Sarmiento, Rafi Ahmed, Shishir K. Maithel, Bassel F. El-Rayes, Gregory B. Lesinski
Summary: Studies show that Hsp90 inhibition can limit inflammatory signals, reprogram the PDAC tumor microenvironment, and enhance sensitivity to PD-1 blockade. Hsp90 inhibitors directly affect PSC/CAF growth and enhance the efficacy of anti-PD-1 blockade in vivo.
MOLECULAR CANCER THERAPEUTICS
(2021)
Review
Oncology
Wenting Du, Marina Pasca di Magliano, Yaqing Zhang
Summary: The stroma-rich, immunosuppressive microenvironment in PDA is characterized by interactions between tumor cells and other cellular components, leading to immune evasion and contributing to cancer cell phenotypes. Therapeutic approaches targeting the stroma and re-programming the tumor microenvironment may improve clinical outcomes for pancreatic cancer patients.
FRONTIERS IN ONCOLOGY
(2021)
Article
Immunology
Changcan Li, Bao Jin, Hang Sun, Yunchao Wang, Haitao Zhao, Xinting Sang, Huayu Yang, Yilei Mao
Summary: The tumor immune microenvironment plays a significant role in tumor progression, metastasis, and therapy. A 3D bioprinted model was created to study the interactions between stromal cells and cholangiocarcinoma cells. The presence of stromal cells in the 3D model enhanced tumor cell activity, showing better proliferation, increased expression of tumor-related genes, and drug resistance.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Engineering, Biomedical
Fang-Yi Lin, Chun-Yi Chang, Han Nguyen, Hudie Li, Melissa L. Fishel, Chien-Chi Lin
Summary: The tumor microenvironment (TME) has crucial effects on pancreatic cancer cell behaviors. In this study, a biomimetic hydrogel with tunable matrix stiffness and stress-relaxation was synthesized to evaluate the effect of matrix viscoelasticity on pancreatic cancer cell behaviors. The results showed that hydrogels with high stress-relaxation promoted the spreading of cancer-associated fibroblasts, which further promoted the proliferation and spreading of pancreatic cancer cells, and upregulated the secretion of soluble proteins known to promote epithelial-mesenchymal transition.
MATERIALS TODAY BIO
(2023)
Article
Oncology
Tao Wang, Jian Yang, Juanli Mao, Lizhi Zhu, Xiu Luo, Chao Cheng, Lu Zhang
Summary: The interaction between pancreatic cancer cells and pancreatic stellate cells plays a crucial role in the aggressive progression of pancreatic cancer. This study found that inhibiting the activity of ITGA5, a protein overexpressed in pancreatic cancer stroma and activated PSCs, impairs the proliferation and migration of PSCs and enhances autophagy. Additionally, ITGA5 inhibition prevents pancreatic cancer cells from acquiring cancer stem cell-like characteristics. These findings suggest that targeting ITGA5 could be a promising therapeutic strategy for pancreatic cancer by disrupting the tumor-stromal crosstalk.
Article
Multidisciplinary Sciences
Rupsa Datta, Sharanya Sivanand, Allison N. Lau, Logan Florek, Anna M. Barbeau, Jeffrey Wyckoff, Melissa C. Skala, Matthew G. Vander Heiden
Summary: The direct interactions between pancreatic stellate cells (PSCs) and cancer cells promote a more oxidized state in cancer cells, overcoming the redox limitations of cell proliferation in pancreatic cancer.
Article
Multidisciplinary Sciences
Hong Cao, Li Qiang, Jing Chen, Katherine M. Johnson, Mark A. McNiven, Gina L. Razidlo
Summary: This study investigates the role of MMPs in tumor cell invasion, particularly focusing on the interplay between MT1-MMP from tumor cells and MMP2 from fibroblasts. The results demonstrate that pro-MMP2 secreted by stromal fibroblasts is activated by MT1-MMP on tumor cells, indicating a key interaction for ECM remodeling and invasion. Depletion of MT1-MMP in tumor cells significantly impairs matrix remodeling, highlighting the importance of this interplay in the metastatic process.