A rectal cancer organoid platform to study individual responses to chemoradiation

Karuna Ganesh, Chao Wu, Kevin P O'Rourke, Bryan C Szeglin, Youyun Zheng, Charles-Etienne Gabriel Sauvé, Mohammad Adileh, Isaac Wasserman, Michael R Marco, Amanda S Kim, Maha Shady, Francisco Sanchez-Vega, Wouter R Karthaus, Helen H Won, Seo-Hyun Choi, Raphael Pelossof, Afsar Barlas, Peter Ntiamoah, Emmanouil Pappou, Arthur ElghouayelJames S Strong, Chin-Tung Chen, Jennifer W Harris, Martin R Weiser, Garrett M Nash, Jose G Guillem, Iris H Wei, Richard N Kolesnick, Harini Veeraraghavan, Eduardo J Ortiz, Iva Petkovska, Andrea Cercek, Katia O Manova-Todorova, Leonard B Saltz, Jessica A Lavery, Ronald P DeMatteo, Joan Massagué, Philip B Paty, Rona Yaeger, Xi Chen, Sujata Patil, Hans Clevers, Michael F Berger, Scott W Lowe, Jinru Shia, Paul B Romesser, Lukas E Dow, Julio Garcia-Aguilar, Charles L Sawyers, J Joshua Smith

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.

Original languageEnglish
Pages (from-to)1607-1614
Number of pages8
JournalNature Medicine
Volume25
Issue number10
DOIs
Publication statusPublished - Oct 2019

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    Ganesh, K., Wu, C., O'Rourke, K. P., Szeglin, B. C., Zheng, Y., Sauvé, C-E. G., Adileh, M., Wasserman, I., Marco, M. R., Kim, A. S., Shady, M., Sanchez-Vega, F., Karthaus, W. R., Won, H. H., Choi, S-H., Pelossof, R., Barlas, A., Ntiamoah, P., Pappou, E., ... Smith, J. J. (2019). A rectal cancer organoid platform to study individual responses to chemoradiation. Nature Medicine, 25(10), 1607-1614. https://doi.org/10.1038/s41591-019-0584-2