Transient targeting of the pancreatic cancer stroma as a ‘fine-tuned’ anti-tumor and anti-metastatic therapy

Pancreatic cancer is one of the deadliest types of cancer, and despite extensive basic and pre-clinical research efforts, existing therapeutics remain largely ineffective. During pancreatic cancer progression, neoplastic transformation of epithelial cells is typically accompanied by a fibrotic response, driven by activation of stromal cells, and which leads to extensive deposition and remodeling of the pancreatic extracellular matrix (ECM) and to reduced tumor vasculature patency [1]. The resulting dense and stiff matrix in turn provides cancer cells with a protective niche, activates potent intracellular signaling pathways, and promotes cell proliferation and invasion while also rendering cancer cells less sensitive to chemotherapies. Consequently, targeting the ECM is considered a valid approach to disrupt pancreatic cancer; however previous attempts to use anti-ECM agents have revealed that the pancreatic tumor ECM can both facilitate and restrain cancer progression, suggesting that there is a delicate balance between the antiand pro-tumor functions of the ECM. Recently, we used multi-photon intravital (in vivo) imaging technologies and high-end mouse and patientderived models of pancreatic cancer to uncover a novel therapeutic approach, whereby transient or pulsed ‘priming’ of the tumor using Fasudil, a pharmacological Rho-kinase inhibitor, leads to a decrease in ECM deposition and remodeling and tips the balance in favor of the anti-tumor properties of the matrix while maintaining normal tissue functions of the organ [2]. As such, the administration of Fasudil as a ‘priming’ agent, rather than chronic treatment, led to improved chemotherapy response in primary and secondary sites; while also reducing metastasis to the liver, and prolonging survival in mice bearing patient-derived orthotopic xenografts (Figure 1A). The ‘priming’ regimen triggered decreased remodeling of the ECM, improved vasculature patency, and subsequently has a dual role in drug targeting (Figure 1B, compare (i) and (iii)). In addition, the altered ECM decreased mechano-signaling mediated through integrin pathways and thus rendered pancreatic cancer cells more sensitive to chemotherapy, likely through a reduction of pro-survival and growth cues provided by the fibrotic pancreatic ECM. Assessment of micro-metastatic events in secondary sites such as the liver revealed that ‘priming’ with Fasudil also impaired cancer cells resistance to shear stress in the circulation, reduced cell streaming and coordinated colonization of the liver, while also blocking ECM remodeling, which is typically required to form a favorable niche at the secondary site (Figure 1A). Together, our work suggests that administration of a ROCK inhibitor as a ‘priming’ agent may be beneficial in the adjuvant and possibly neo-adjuvant settings in pancreatic cancer [2, 3]. This may prove to be a significant advance in the field of stromal targeting in pancreatic cancer, as previous studies have demonstrated that complete ablation of fibrosis Editorial