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2024 - Titia de Lange

Motivation
De Lange is being recognized for discovering the molecular mechanisms by which telomeres protect chromosome ends, characterizing the function of the shelterin protein complex, and demonstrating how loss of telomere protection results in aberrant genomic integrity and tumorigenesis.

De Lange’s research has brilliantly elucidated the role of telomeres—regions of repetitive nucleotide sequences at the ends of chromosomes—in cancer onset and progression, mainly through work that has defined the role of the shelterin protein complex in protecting telomeric DNA by blocking DNA damage and repair activity.

In 1995, through the use of elegant biochemistry approaches, de Lange identified and cloned the first telomeric mammalian protein of the shelterin complex (TRF1), defining its role in the inhibition of telomeric DNA elongation. Later, de Lange identified four additional shelterin complex proteins (TRF2, TIN2, Rap1, and TPP1) that, together with TRF1 and POT1, are responsible for telomere protection. Through a series of groundbreaking experiments using murine knockout models, de Lange and her collaborators characterized the fate of telomeres lacking one or more shelterin complex subunits, demonstrating that cells perceive chromosome ends as damaged DNA when shelterin is compromised, as shelterin is able to inhibit six different DNA damage response mechanisms. De Lange’s research showed that in the absence of shelterin, there is aberrant double-stranded DNA damage repair, resulting in the induction of cell death and/or cellular senescence via the ATM and ATR kinase signaling pathway.

In addition, de Lange and her collaborators made a major molecular biology discovery with the identification of the t-loop structure of telomeres, whereby a single-stranded overhang is inserted into the double-stranded repeat array of the telomere. This structure protects the telomere end from DNA damage responses, a mechanism orchestrated by TRF2.

De Lange also uncovered a potential cancer-causing mechanism with the observation that telomere shortening leads to genomic instability in cells with mutations in TP53, a gene that is mutated in half of all cancers. Given that telomere lengthening can lead to cancer, de Lange investigated and later found that the POT1, TIN2, and TRF1 shelterin complex proteins may help prevent cancer by blocking the activity of the telomere-lengthening protein telomerase.

Collectively, de Lange’s research has had direct and profound clinical implications, highlighted by one of her more recent discoveries that individuals with germline mutations in TIN2 are born with extremely long telomeres and present with an increased risk of developing cancer.

Dr. de Lange’s pioneering research has greatly increased our understanding of how a cell responds when its DNA is damaged,” said Margaret Foti, PhD, MD (hc), chief executive officer of AACR. “Dr. de Lange is a world-renowned expert in how telomeres protect chromosome ends, and her groundbreaking research has provided crucial scientific insights into the development and progression of cancer. The Pezcoller Foundation and the AACR are thrilled to honor her with this prestigious award.”


“We are especially happy and proud that the Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research has been given this year to Dr. de Lange for her highly impactful research on telomeres that has defined the role of the shelterin protein complex in cancer initiation and progression,” said Enzo Galligioni, MD, president of the Pezcoller Foundation. “The Pezcoller Foundation, in partnership with AACR, has been recognizing the best cancer researchers with this award for more than 25 years—including three future Nobel laureates. It is notable that the research that earned Dr. de Lange this year’s prize is in telomeres. In 2001, Dr. Elizabeth Blackburn won the Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research for her trailblazing work in the same field; in 2009, she received the Nobel Prize in Physiology or Medicine for her discoveries.”


Dr. Titia de Lange, winner of the 2024 Pezcoller Foundation - AACR Award for Extraordinary Achievement in Cancer Research

About the Winner
De Lange is Leon Hess Professor, head of the Laboratory of Cell Biology and Genetics, and director of the Anderson Center for Cancer Research at The Rockefeller University in New York.

De Lange was elected as a
Fellow of the AACR Academy in 2014. She received the AACR-G.H.A. Clowes Award for Outstanding Basic Cancer Research in 2010 and the AACR-Women in Cancer Research Charlotte Friend Lectureship in 2004.

De Lange’s scientific achievements have been recognized with numerous awards and honors, including the Karl Friedrich Bonhoeffer Award (2022); Mike Hogg Award (2019); Bert and Natalie Vallee Award in Biomedical Science (2018); Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science (2017); National Cancer Institute (NCI) Outstanding Investigator Award (2016); Canada Gairdner International Award (2014); Jill Rose Award (2013); Katharine Berkan Judd Award (2013); Breakthrough Prize in Life Sciences (2013); Royal Netherlands Academy of Sciences Heineken Prize for Biochemistry and Biophysics (2012); Vilcek Prize for Creative Promise in Biomedical Sciences (2011); NCI Rosalind Franklin Award (2012); Vanderbilt Prize in Biomedical Science (2011); American Cancer Society Research Professor Award (2010); Massachusetts General Hospital Cancer Center Prize (2008); The Rockefeller University Distinguished Teaching Award (2007); National Institutes of Health Director’s Pioneer Award (2005); and the Paul Marks Prize for Cancer Research (2001).

De Lange is also an elected foreign member of the Royal Society (2022); an elected member of the National Academy of Medicine (2010) and Royal Dutch Academy of Sciences (2000); an elected Fellow of the American Association for the Advancement of Science (2007), American Academy of Arts and Sciences (2007), and American Academy of Microbiology (2006); and an elected international member of the National Academy of Sciences (2006).

She earned her PhD in biochemistry at the University of Amsterdam and The Netherlands Cancer Institute.

De Lange’s award lecture will be presented on Sunday, April 7, during the AACR Annual Meeting 2024 in San Diego.

The traditional Award Ceremony will be held on Saturday, May 11, 2024, 10 a.m. in Trento, at the Teatro Sociale, in the presence of the authorities and representatives of the Trentino scientific, academic and business community. The citizenry is cordially invited: the event is free and open to all.

On the two days preceding the ceremony, Prof. de Lange will give two Lectures at the Universities of Trento and Padua.



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