2. Academic Validation
  3. Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy-induced toxicities

Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy-induced toxicities

  • Sci Adv. 2022 Nov 11;8(45):eabn6579. doi: 10.1126/sciadv.abn6579.
Johan K E Spetz 1 2 3,  Mary H C Florido 1 2 3 4 5,  Cameron S Fraser 1 2 3,  Xingping Qin 1 2 3,  Jonathan Choiniere 1 2 3,  Stacey J Yu 1 2 3,  Rumani Singh 1 2 3,  Max Friesen 4 5,  Lee L Rubin 4 5,  Joe-Elie Salem 6 7,  Javid J Moslehi 8,  Kristopher A Sarosiek 1 2 3 9
Affiliations

Affiliations

  • 1 John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 2 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • 3 Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 4 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • 5 Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
  • 6 Clinical Investigation Center Paris-Est, CIC-1901, INSERM, UNICO-GRECO Cardio-Oncology Program, Department of Pharmacology, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France.
  • 7 Cardio-Oncology Program, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 8 Section of Cardio-Oncology and Immunology, Division of Cardiology and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Cancer Center, Boston, MA, USA.
PMID: 36351019 DOI: 10.1126/sciadv.abn6579
Abstract

Although major organ toxicities frequently arise in patients treated with cytotoxic or targeted Cancer therapies, the mechanisms that drive them are poorly understood. Here, we report that vascular endothelial cells (ECs) are more highly primed for Apoptosis than parenchymal cells across many adult tissues. Consequently, ECs readily undergo Apoptosis in response to many commonly used Anticancer agents including cytotoxic and targeted drugs and are more sensitive to ionizing radiation and BH3 mimetics than parenchymal cells in vivo. Further, using differentiated isogenic human induced pluripotent stem cell models of ECs and vascular smooth muscle cells (VSMCs), we find that these vascular cells exhibit distinct drug toxicity patterns, which are linked to divergent therapy-induced vascular toxicities in patients. Collectively, our results demonstrate that vascular cells are highly sensitive to apoptosis-inducing stress across life span and may represent a "weakest link" vulnerability in multiple tissues for development of toxicities.

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