Reprogramming Immunosuppressive Bone Marrow Derived Cells via CD44 Targeting Impacts Pancreatic Cancer Metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by early dissemination and an aggressive metastatic course. In order to establish in the liver, metastatic cells require a metastatic niche providing pro-survival signals. Here, we demonstrate that bone marrow-derived cells (BMDCs) establish immunosuppressive niches in the liver that promote metastatic colonization in PDAC. Using an immunocompetent orthotopic PDAC mouse model, we show that BMDCs form clusters enriched in myeloid progenitors and display upregulation of migratory, adhesive, and immunoregulatory programs in response to tumor-derived cues. CD44 and its splice variant CD44v6 are found to be highly expressed on these cells. Hematopoietic-specific deletion of Cd44 or Cd44v6 using Cd44/Cd44v6fl/fl;VavCreERT2mice markedly impairs BMDC clustering, reshapes the BMDC transcriptome, disrupting pathways critical for migration, adhesion, and immunosuppression thereby reducing metastatic burden. Mechanistically, CD44 inhibition blocks BMDC migration toward CCL2, CCL5, and CXCL12, and impairs adhesion to VCAM-1 and fibronectin. Functionally, Cd44-deficient BMDCs exhibit reduced expression of immunosuppressive mediators such as Arginase 1, Ido1, and Il10, and fail to suppress T cell proliferation. Our findings position CD44 as a pleiotropic regulator of BMDC-mediated metastatic niche formation and identify it as a promising therapeutic target to disrupt the pro-metastatic microenvironment in PDAC.