Abstract A010: Chemotherapy-associated liver damage accelerates pancreatic cancer liver metastasis

Pancreatic cancer outcomes remain dismal, even for the ∼15-20% of patients that present with early-stage, surgically resectable disease. Most patients that undergo months of neoadjuvant chemotherapy followed by pancreaticoduodenectomy will recur with metastases within a few years. These clinical challenges illustrate the fact that pancreatic tumor cells spread to distant organs early in disease, and to mitigate metastasis progression, there is a profound need for therapies that target disseminated tumor cells (DTCs). Our studies demonstrate that systemic oxaliplatin (oxali) treatment, a chemotherapy included in the standard-of-care therapy FOLFIRINOX, generates a pro-metastatic liver environment that accelerates pancreatic cancer liver metastasis outgrowth and reduces overall survival in a mouse model. Proteomic analysis of liver interstitial fluid revealed that oxali drives increased expression of Tissue Inhibitor of Metalloproteinases 1 (Timp1). Surgically resected pancreatic cancer patients that recur early have higher serum TIMP1 expression levels at the time of surgery than those that recur late or don’t recur, suggesting that TIMP1 may functionally contribute to metastasis in patients. Furthermore, genetic or pharmacologic blockade of Timp1 reverses the accelerated metastasis phenotype caused by oxali treatment and extends survival in mouse models of pancreatic cancer liver metastasis. Mechanistically, Timp1 is a pleiotropic extracellular protein with multiple functions, including inhibiting matrix metalloproteinases (MMPs) and serving as a cytokine that binds and activates transmembrane receptors. We demonstrate that oxali-damaged livers have decreased functional MMPs, and micrometastases that seed oxali-damaged livers have increased matrix deposition and stiffness. Further, exogenous TIMP1 directly activates Akt-Rheb signaling cascades in pancreatic cancer cells, leading to enhanced migratory and invasive phenotypes. Single-cell sequencing analysis of livers revealed TIMP1 is highly expressed in liver endothelial cells and fibroblasts. Pancreatic cancer cells exposed to conditioned-media from oxali-treated fibroblasts display enhanced migration, which is mitigated in conditioned media from Timp1-suppressed fibroblasts. Taken together, our studies reveal a concerning link between chemotherapy and generation of a Timp1-enriched pro-tumorigenic liver microenvironment capable of promoting metastatic outgrowth. We propose that disrupting Timp1 would serve to reduce recurrence with liver metastasis in surgically-resected patients. Citation Format: Omar Cortez-Toledo, Kai Liptow, Priyanga Jayakrishnan, Isabella Facchine, Kun Fang, Donovan Drouillard, Michael Poellmann, Mohammed Aldakkak, Susan Tsai, Victor Jin, Michael Dwinell, Nikki Lytle. Chemotherapy-associated liver damage accelerates pancreatic cancer liver metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A010.