Evolutionary conserved reciprocal senescence and tumor suppressor signals limit lifetime cancer

Liu, L.; Davis, S.; Yusuff, S.; Strange, A.; Zhuang, Y.; Vaddi, P.; Flaherty, K.; Jara, K.; Kramer, J.; Archer, C.; Lee, S.; Gao, B.; van Bokhoven, A.; Wang, W.; Pine, S. R.; Nakamura, T.; Sabaawy, H. E.

doi:10.1101/2024.12.28.630560

bioRxiv · 10.1101/2024.12.28.630560

Evolutionary conserved reciprocal senescence and tumor suppressor signals limit lifetime cancer

Liu, L.·Davis, S.·Yusuff, S.·Strange, A.·Zhuang, Y.·Vaddi, P.·Flaherty, K.·Jara, K.·Kramer, J.·Archer, C.·Lee, S.·Gao, B.·van Bokhoven, A.·Wang, W.·Pine, S. R.·Nakamura, T.·Sabaawy, H. E.

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Abstract

Cellular senescence features a durable exit from the cell cycle triggered by stress or carcinogens. The INK4 locus is inactivated in various cancers, yet in senescence, p16Ink4a is activated. Whether senescence is tumor-suppressing or -promoting remains a conundrum. We discovered an evolutionally-conserved Vertebrata INK4-homolog. This ink4ab triggers senescence upon oxidative- and/or carcinogenic-stress. Adult Ink4ab-deficient animals failed to activate senescence and developed spontaneous cancers. Combined Ink4ab and Tp53 deficiency revealed a reciprocal senescence and apoptosis regulation, controlling tumorigenesis, including retinoblastoma. INK4-hematopoietic-deficient mice exhibited p19Arf-dependent enhanced senescence-like phenotypes, uncontrolled cell proliferation, defective stem cell differentiation, and splenomegaly, with single-splenocytes spatially-enriched in senescence-associated secretory profiles. Our studies reveal the evolutionary origin of paradigms co-regulating senescence and tumor suppression and offer strategies to exploit these reciprocal pathways for cancer prevention and therapy.

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Liu, L., Davis, S., Yusuff, S., Strange, A., Zhuang, Y., Vaddi, P., Flaherty, K., Jara, K., Kramer, J., Archer, C., Lee, S., Gao, B., van Bokhoven, A., Wang, W., Pine, S. R., Nakamura, T., Sabaawy, H. E.. 2024-12-29. Evolutionary conserved reciprocal senescence and tumor suppressor signals limit lifetime cancer. https://doi.org/10.1101/2024.12.28.630560

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