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.