Advancing cancer research via comparative oncology

Abstract

In the ongoing battle against cancer, the natural world provides promising inspiration for designing novel therapeutic strategies. The field of comparative oncology offers a valuable source of such inspiration. By combining evolutionary biology, ecology, veterinary medicine and clinical oncology, comparative oncology aims to better understand cancer, especially by highlighting taxa that are strongly resistant or susceptible to cancer and to identify the molecular and cellular mechanisms underlying the remarkable cancer resistance of some taxa. Such studies hold profound implications for human cancer research and treatment, and increase the probability of detecting therapeutic avenues that are non-toxic to healthy cells and tissues. This Perspective underscores the importance of comparative oncology, emphasizes its relevance, and showcases recent breakthroughs in identifying natural cancer resistance mechanisms and opportunities for clinical translation. We advocate for a better integration of cancer research on non-conventional model species into oncology and we urge enhanced cooperation between clinicians and comparative oncologists to advance cancer prevention or treatment strategies.

Figure. 1.. Diverse cancer resistance mechanisms of organisms across the tree of life

Animals exhibit diverse proposed cancer resistance mechanisms, including DNA protection (e.g. e.g. efficient genotoxic drug efflux mediated by the ATP-binding cassette transporters in bats protects the DNA), efficient DNA repair (e.g., high levels of cold-inducible RNA-binding protein (CIRBP) and replication protein A2 (RPA2) are present in bowhead whale fibroblasts and increase the efficiency and fidelity of DNA repair), effective elimination of damaged cells (e.g., high rates of p53-mediated apoptosis in response to DNA damage in elephants), preventing clonal expansion of pre-malignant cells (e.g., naked mole rat fibroblasts secrete extremely high molecular weight hyaluronan acting as signal to CD44 receptors and triggering early contact inhibition), elimination of over-proliferating pre-malignant cells (e.g. blind mole rat cells express very low levels of DNA methyltransferase 1 that fails to maintain DNA methylation on retrotransposable elements during rapid cell proliferation; derepression of RTEs triggers the formation of cytoplasmic RNA-DNA hybrids, which activate the cGAS-STING pathway and induce concerted cell death), and removal of cancer cells via cell competition (e.g., in fruit flies, genetically fitter cells eliminate neighboring abnormal cells, such as those with mutations or altered polarity, through apoptosis triggered by signaling imbalances, innate immune responses, or mechanical stress).