The purpose of this study is to investigate whether a subpopulation of cancer associated fibroblasts (CAFs) are responsible for mechanosensation-mediated chemoresistance in pancreatic adenocarcinoma (PDAC). PDAC is one of the most lethal types of cancer with few effective treatments. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there are few easily tunable models to recapitulate this stiff microenvironment. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this biomimetic model and a mechano-sensation-dependent reporter, we have identified a unique subpopulation of CAFs responsible for mechano-sensing the fibrotic matrix and facilitating CAF-mediated chemoresistance. Moreover, these mechanosensitive CAFs (mecCAFs) respond to increased stiffness through YAP-mediated pathways. Our results also demonstrate how ECM stiffness affects chemoresistance via the hypersecretion CAF-derived exosomes. Moving forward, therapies designed to interrupt the function of mecCAFs could be utilized to overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Weian Zhao, Reginald Hill. Identification of mechanosensitive cancer associated fibroblasts in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5848.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with few effective treatments. Despite recent advances in in other cancers, the five-year survival rate of PDAC is still only 10%, with most patients succumbing to their disease within the first year. One of the main factors responsible for this poor outcome is the development of chemoresistance in nearly all clinical cases. While the intrinsic factors that facilitate chemoresistance in the tumor cells have been studied extensively, fewer studies have elucidated how the complex and unique microenvironment surrounding the tumor affects therapeutic responses. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there is a lack of high-throughput, easily tunable models to recapitulate this complex microenvironment, in order to identify a critical cell-extrinsic factors that could drive acquired chemoresistance in PDAC cells. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this system, we found that matrix-activated CAFs readily remodel the desmoplastic matrix through lysol-oxidase dependent crosslinking. Moreover, our novel system demonstrates how collagen-I and matrix stiffness affect chemoresistance via the hypersecretion CAF-derived exosomes. Interestingly, our data show that it is CAF-derived exosomes, not the organoid-derived exosomes, that are most important in regulation of proliferation and chemoresistance. Lastly, we identified key cell surface integrins for collagen-I as therapeutic targets to prevent desmoplastic matrix-mediated chemo-resistance in PDAC. Our study provides insights into how matrix composition and stiffness affect therapeutic outcome in PDAC. Moving forward, therapies aimed at interrupting how PDAC cells and stomal cells sense the matrix microenvironment could be utilized to eventually overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, Reginald Hill. Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1567.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and malignant type of cancer with few effective treatments. Despite recent advancement in knowledge of cancer treatment, median survival of PDAC patients remains within 2 years, and less than 8% patients live beyond 5 years after diagnosis. The main factor that drives PDAC lethality is the development of chemoresistance in nearly all clinical PDACs. While intrinsic factors that facilitates chemoresistance have been studied extensively, few studies have illustrated how complex and unique microenvironment surrounding the PDAC tumor affects therapeutic responses. Moreover, a physiologically relevant co-culture model of PDAC and stromal cells remained challenging. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to culture established human PDAC cell lines, cancer-associated fibroblast (CAF) cells and mouse model-derived organoids. Individual matrix parameters can be customized to mimic actual tumor matrix composition and mechanical properties. Moreover, we have optimized a co-culture medium to maintain viability of both organoid tumor and cancer associated fibroblasts. Through our 3D culture system, our data suggests that matrix-induced exosome secretion directly facilitate gemcitabine resistance in PDAC cells. By directly increasing stiffness of our 3D culture platform, we have observed that PDAC cells potentially display more invasive phenotype. Moreover, in the co-culture systems, we have seen that CAF cells cultured in different stiffness substrates affect PDAC drug response in organoid cultures. Our investigation provides insight into how matrix composition and stiffness together affect therapeutic outcome in PDAC. We believe that specific therapeutic strategies aimed at targeting the matrix microenvironment will be instrumental in order to overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Charlene Dekalb, Kexin Zhang, Reginald Hill. Investigation of how extracellular matrix composition affects pancreatic cancer chemoresistance through the use of biomimetic models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5108.
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