Abstract B072: Pharmacological depletion of fibrinogen suppresses the growth of primary tumors and liver metastasis of pancreatic cancer
Authors: Chowdhury Nayela N , Mitchell Dana K , Kangro Kadri , Eldridge Kierra , Abrahams Sara , Ferraresso Francesca , Juang Lih J , Gampala Silpa , Brewster Kylee , Revenko Alexey , Kastrup Christian , Territo Paul R , Clapp D Wade , Belgodere Jorge A , Han Bumsoo , Wolberg Alisa S , Zhang Chi , Flick Matthew J , Fishel Melissa L 
Published: September 2024

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly metastatic disease often linked to the dysregulated activation of both coagulation and fibrinolytic systems. Clinically, patients show elevated plasma fibrinogen levels, particularly in those with distant metastasis. The presence of systemic fibrinogen plays a crucial role in shaping the complex tumor microenvironment (TME) characteristic of PDAC, evidenced by the excessive deposition of its active substrate, fibrin, in PDAC tumors. To investigate its contribution to disease progression, fibrinogen (Fib) was depleted from the TME in three PDAC mouse models, and the impact on tumor growth and metastasis was followed. In an aggressive, metastatic orthotopic Pa03C model, Fib depletion using antisense oligonucleotide (ASO) treatment markedly decreased the size of primary pancreatic tumors and subsequent spontaneous metastasis to the liver. Following implantation of tumor chunks from two different patients (PDX21 and PDX33), Fib depletion significantly diminished growth of primary orthotopic tumors significantly compared to control. This confirms that Fib deposition within the TME is an important driver of disease progression. Mechanistically, global proteomics revealed a remarkable upregulation of matrisome and extracellular matrix (ECM)-associated proteins, indicating that the reduction in primary orthotopic Pa03C tumors was associated with fibrin-mediated TME remodeling. Loss of fibrin matrices led to enhanced collagen, laminin, fibronectin and emilin-1 deposition, and increased presence of collagen-producing αSMA+ myofibroblasts. Spatial transcriptomics of these tumors supported this data and demonstrates an increased presence of stromal cells within the tumors from Fib-depleted mice. Notably, our data shows that fibrinogen depletion altered the ECM composition, inducing TME remodeling which led to stiffer tumors that are less metastatic. To further interrogate the role of Fib in mediating metastasis, an experimental metastasis model using intrasplenic injection of tumor cells to colonize the liver was used. In this additional model, Fib depletion did not impede the colonization of tumor cells within the liver, suggesting that Fib remodels the TME within the primary tumor which results in less tumor cells in the liver and is likely involved in one of the earlier steps of metastasis. Our data showed that pharmacologically reducing systemic fibrinogen levels impeded tumor growth and liver metastasis by preventing the formation of fibrin clots within the tumor macroenvironment which led to remodeling of the tumor and the TME. Additionally, Fib facilitates interactions between tumor cells and the extracellular matrix, promoting tumor cell survival and spread. By depleting fibrinogen, these interactions were disrupted, limiting the ability of the tumor to grow and metastasize. Our findings suggest a new avenue for clinical translation- integrating inhibitors targeting fibrinogen into chemotherapy regimens to cumulatively control the spread of pancreatic cancer.
Citation Format: Nayela N Chowdhury, Dana K Mitchell, Kadri Kangro, Kierra Eldridge, Sara Abrahams, Francesca Ferraresso, Lih J Juang, Silpa Gampala, Kylee Brewster, Alexey Revenko, Christian Kastrup, Paul R Territo, D Wade Clapp, Jorge A Belgodere, Bumsoo Han, Alisa S Wolberg, Chi Zhang, Matthew J Flick, Melissa L Fishel. Pharmacological depletion of fibrinogen suppresses the growth of primary tumors and liver metastasis of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B072.