Pancreatic cancer organoids recapitulate disease and allow personalized drug screening

Driehuis, Else; Van Hoeck, Arne; Moore, Kat S.; Kolders, Sigrid; Francies, Hayley E; Gulersonmez, M. Can; Stigter, Edwin C A; Burgering, Boudewijn M.T.; Geurts, Veerle; Gracanin, Ana; Bounova, Gergana; Morsink, Folkert H M; Vries, Robert GJ; Boj, Sylvia Fernandez; van Es, Johan H; Offerhaus, G Johan A; Kranenburg, Onno; Garnett, Mathew J.; Wessels, Lodewyk F.A.; Cuppen, Edwin; Brosens, Lodewijk A. A.; Clevers, Hans

doi:10.1073/pnas.1911273116

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Pancreatic cancer organoids recapitulate disease and allow personalized drug screening

Author(s): Else Driehuis , Arne van Hoeck , Kat Moore , Sigrid Kolders , Hayley E. Francies , M. Can Gulersonmez , Edwin C. A. Stigter , Boudewijn Burgering , Veerle Geurts , Ana Gracanin , Gergana Bounova , Folkert H. Morsink , Robert Vries , Sylvia Boj , Johan van Es , G. Johan A. Offerhaus , Onno Kranenburg , Mathew J. Garnett , Lodewyk Wessels , Edwin Cuppen , Lodewijk A. A. Brosens , Hans Clevers

Publication date Created: December 26 2019

Publication date (Electronic): December 09 2019

Journal: Proceedings of the National Academy of Sciences

Publisher: Proceedings of the National Academy of Sciences

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Abstract

We report the derivation of 30 patient-derived organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical of pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic, and underscores the importance of personalized approaches for effective cancer treatment. The PRMT5 inhibitor EZP015556, shown to target MTAP(a gene commonly lost in pancreatic cancer)-negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP-positive tumors. Taken together, the work presented here provides a platform to identify novel therapeutics to target pancreatic tumor cells using PDOs.

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William A Freed-Pastor, Carol Prives (2012)

There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.

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Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression

Shinya Sugimoto, Eisuke Iwasaki, Junichi Takagi … (2018)

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Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations

David Tamborero, Carlota Rubio-Perez, Jordi Deu-Pons … (2018)

While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Here we present the Cancer Genome Interpreter, a versatile platform that automates the interpretation of newly sequenced cancer genomes, annotating the potential of alterations detected in tumors to act as drivers and their possible effect on treatment response. The results are organized in different levels of evidence according to current knowledge, which we envision can support a broad range of oncology use cases. The resource is publicly available at http://www.cancergenomeinterpreter.org. Electronic supplementary material The online version of this article (10.1186/s13073-018-0531-8) contains supplementary material, which is available to authorized users.