Dissecting inflammatory microenvironments during aging and their effect on the development of chronic blood cancer

RWTH Publications (RWTH Aachen)

Abstract

Cancer-associated bone remodeling is traditionally viewed as a unidirectional process leading either to pathological bone formation or bone loss. Myeloproliferative neoplasms (MPNs), a group of hematologic cancers predominantly driven by the JAK2V617F mutation, provide a unique model in which oncogenic hematopoiesis profoundly reshapes the skeletal microenvironment, resulting in bone marrow fibrosis (myelofibrosis) and osteosclerosis. This phenotype has historically been attributed to impaired osteoclast function. In this thesis, we challenge this paradigm and demonstrate that a single oncogenic hematopoietic clone can simultaneously drive pathological bone formation and active bone destruction in a niche- and ontogeny-dependent manner. Rather than preventing bone loss, osteosclerosis conceals spatially restricted osteolytic remodeling. Through an interdisciplinary strategy integrating population-level analyses, clinical imaging, patient-derived single-cell multi-tissue sequencing, murine models, and human organ-on-a-chip systems, we uncover a bidirectional interaction between MPN and periodontal disease. We identify a previously unrecognized osteochondral stromal injury program shared across mesoderm- and neural crest–derived bones. This remodeling response is mediated by a conserved Thrombospondin-1–expressing (Thbs1⁺) stromal population that functionally links fibrotic remodeling to bone degeneration. Combined pharmacological inhibition of Thbs1 and JAK2 signaling synergistically restores both osteosclerotic and osteolytic skeletal abnormalities, establishing Thbs1 as a unifying and disease-modifying target in myelofibrosis. Importantly, periodontal inflammation reciprocally aggravates malignant hematopoiesis, rewires the bone marrow stem cell compartment, and primes fibrotic transformation. To mechanistically model this systemic crosstalk, we developed a human multi-organ-on-a-chip platform that recapitulates inflammation-induced hematopoietic remodeling and enables real-time tracking of mutant immune cell mobilization toward distant inflammatory tissues. Collectively, these findings challenge the concept of uniform tissue responses driven solely by oncogenic signaling and instead define stromal ontogeny and lineage plasticity as central regulators of cancer-associated bone pathology.

Authors 1

1. Salim Atakhanov corresponding Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen