A temporal coupling hypothesis for chemoresistance in canine DLBCL and osteosarcoma: stress signalling and microRNA regulation

Acquired chemoresistance remains a major clinical problem in canine diffuse large B-cell lymphoma (DLBCL) and osteosarcoma. Existing canine studies identify established resistance-associated features, including drug efflux, altered apoptosis, DNA repair, epigenetic change, and microRNA (miRNA) dysregulation, and support selected stress-response components as biologically relevant. However, the available canine evidence does not establish a chemotherapy-induced temporal sequence linking early stress signalling to later miRNA regulation. Likewise, the YAP-DDX17-Microprocessor relationship is supported by mechanistic evidence from mammalian/human systems but has not been demonstrated as a chemotherapy-induced coupling mechanism in canine tumours. This Opinion Paper therefore presents a testable temporal coupling hypothesis rather than a validated canine mechanism. The hypothesis asks whether early treatment-induced stress responses reproducibly precede and are associated with later miRNA regulation, and whether any such relationship reflects mechanistic dependence. YAP-DDX17-Microprocessor is considered one experimentally tractable but unvalidated candidate bridge, not a required component of the broader hypothesis. The article distinguishes established canine evidence from cross-species evidence and theoretical inference, and outlines the longitudinal and perturbational studies needed to test the hypothesis while accounting for pharmacokinetics, miRNA biogenesis, and tumour-microenvironment effects before clinical translation.