Angelika Amon (1967–2020)
Authors: Charles Swanton
Journal: Cancer Cell (2020)

Angelika Amon was born in Vienna in 1967. Black-and-white time-lapse images of chromosomes from dividing plant cells at school, together with her learnings in Mendelian genetics, kindled her lifelong interest in the mechanisms of cell division and the segregation, and mis-segregation, of chromosomes to daughter cells and the impact of her findings on human health. Similar to Theodor Boveri, a German zoologist a century before her, who she often cited in manuscripts and talks, Angelika was fascinated by the delicate orchestration of cell division and the coordination of chromosome segregation during mitosis. Unknown to her during her school years, she would go on to decipher several players of this orchestra as well as answers to fundamental biological questions central to cell division and tumorigenesis posed by Boveri and more widely by the scientific community over the next 100 years. Angelika’s early years in research at the University of Vienna and at the Institute of Molecular Pathology, mentored by Kim Nasymth, allowed her to develop her passion for the cell cycle. She unraveled differing dependencies for tyrosine 19 dephosphorylation of p34Cdc28 in eukaryotic organisms prior to the onset of mitosis from G2 and developed a deeper understanding of the mechanistic basis for the oscillatory patterns of G1- and G2-specific cyclins through cell cycle regulated proteolysis. In 1994, Angelika moved to the Whitehead Institute as a postdoctoral fellow in the laboratory of Ruth Lehmann, working with Drosophila. She was appointed a Whitehead Fellow in 1996, enabling her to return to her primary calling, yeast genetics. This catalyzed her independent career and in 1999 a faculty appointment in MIT in the Department of Biology and Center for Cancer Research, which later became the Koch Institute. During her early independent career, she rapidly established mechanisms of cell cycle exit from mitosis into G1 mediated by the phosphatase Cdc14, defined Cdc20 as the key target of the spindle assembly checkpoint in mitosis, and established the regulation of yeast mitotic cyclin and securin breakdown through activation of anaphase-promoting complex (APC)-dependent proteolysis by Cdh1 and Cdc20. However, her work was not limited to furthering the understanding of the normal function of the cell cycle. Over the last 15 years, Angelika turned her cell cycle skills to studying one of life’s important mysteries: What happens when a cell fails to faithfully segregate its chromosomes? What is the impact on the resulting daughter cells following a chromosome mis-segregation event? And could vulnerabilities and dependencies resulting from the state of an abnormal chromosome number (aneuploidy—a cancer hallmark) be exploited clinically to treat cancers? Angelika pioneered the study of the phenomenon of alterations in chromosome number resulting from aberrations in cell division that are pervasive in cancer. Through yeast and mammalian cell experiments, she revealed the stresses that aneuploidy places upon normal cells. Her group established that aneuploidy results in impaired cell cycle progression and proliferation and in increased glucose uptake and sensitivity to stresses affecting protein folding and synthesis. Intriguingly, these shared phenotypes are independent of the extra chromosomes gained. Deservedly, Angelika was made a full professor around this time, the Kathleen and Curtis Marble Professor in Cancer Research, and an investigator of the Howard Hughes Medical Institute. These findings led her to question whether drugs could be identified that could exploit vulnerabilities in aneuploid cells, finding that the combination of AICAR (an AMPK activator) and 17-AAG (an HSP90 inhibitor that would affect protein folding) selectively drive the death of aneuploid cancer cells. Later her group showed that aneuploidy renders cancer cells vulnerable to immune cell-mediated predation through upregulation of NKG2D ligands that trigger NK cell activation. So why is aneuploidy so common in cancer and often associated with complex chromosome rearrangements? First, in budding yeast, her group demonstrated the genome-destabilizing impact of aneuploidy, which increases chromosome loss and mitotic recombination and impairs DNA damage repair in yeast strains harboring one extra chromosome. Through elegant experiments in mouse embryonic fibroblasts engineered to have an extra chromosome, her group found, as expected from her earlier work, that such cells were less fit in xenograft models compared to their euploid controls grown under similar conditions. However, intriguingly, over time, trisomic cells acquired further chromosomal abnormalities not present in the euploid cells, which were associated with improved fitness. Taken together, her work supported the view that while initially aneuploidy is tumor suppressive, the “genome-destabilizing” impact of chromosome mis-segregation opens up evolutionary opportunities for the cell to gain fitness over time. Her work revealed that aneuploidy also causes non-genetic phenotypic heterogeneity, in part resulting from copy number imbalances across genes that might impact finely tuned biological networks, manifesting as phenotypic diversity when impacting many genes. The findings from this body of work have contributed significantly to our understanding of why aneuploidy is so prevalent in human cancers; while aneuploidy might negatively affect cell division initially, over time it permits cellular evolution and adaptation. Angelika received numerous awards, including the prestigious Presidential Early Career Award (1998), the Paul Marks Prize for Cancer Research (2007), the Vilcek Prize (2019), and the Breakthrough Prize (2019). Vilcek and Nair perfectly summarize the reasons for these numerous prestigious awards: her “crystalline insights into life’s elemental problems.” Angelika never lost her zest for discovery and mentorship. Angelika was a major proponent of supporting fundamental biological research to drive medical breakthroughs, and her career perfectly exemplified its critical importance. She was fearless, not just in her approach to scientific challenges but also in her efforts to address inequalities in scientific career progression between men and women. Angelika was widely regarded by those who knew her or trained with her as a force for good as well as a force of nature in biological sciences, described as a “devoted mentor,” “a fantastic person,” “a lively and spirited colleague and an incredible and creative scientist.” She supervised over 80 postdoctoral fellows, graduate students, and undergraduate students during her career. “If you worked for her, she changed your life.” “Brilliant, rigorous, hilarious, badass.” She cared very deeply about those who trained with her, and her legacy of highly successful “Amonites” was fostered thanks to her devoted oversight. Angelika died on October 29, 2020, following a prolonged illness with ovarian cancer, a disease characterized by profound chromosomal instability that she dedicated her career to understanding. Her legacy is profound. Thanks to her life’s work, we are undoubtedly closer to exploiting aneuploidy to benefit patients with cancer. Angelika’s scientific discoveries will continue to guide and instruct cancer and cell biologists through the 21st century, much as Boveri’s work did the century before.