【AI Explained】Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases.

Literature Information

TL;DR

This study demonstrates that tumor organoids can be successfully cultured from metastatic colorectal cancer biopsies, achieving a 71% success rate, and reveals that these organoids maintain the genetic diversity of the original tumors, with 90% of somatic mutations shared between them. These findings highlight the potential of patient-derived organoids as a valuable ex vivo platform for personalizing cancer treatment.

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DNA sequencing · biopsy-derived tumor organoids · colorectal cancer · copy number analysis · personalized medicine

Abstract

Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment.

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Primary Questions Addressed

1. What implications does the genetic diversity of organoids have on the development of personalized treatment strategies for colorectal cancer?
2. How does the success rate of 71% in establishing organoid cultures from metastatic biopsies compare to other cancer types?
3. What specific genetic mutations were identified in the organoids that were not present in the original tumor biopsies, and what is their significance?
4. How can the findings regarding the correlation of DNA copy number profiles influence future research on tumor evolution and treatment resistance?
5. What are the potential limitations of using patient-derived organoids for drug testing in metastatic colorectal cancer cases?

Key Findings

Research Summary

Background and Objective

The study investigates the feasibility of culturing organoids from biopsies of metastatic colorectal cancer (mCRC) and evaluates whether these organoids maintain the genetic diversity present in the original tumors. The primary aim is to establish a reliable ex vivo platform for personalized cancer treatment based on individual tumor characteristics.

Main Methods/Materials/Experimental Design

The study involved the following key components:

• Study Design: A prospective analysis of 14 patients with metastatic colorectal cancer who underwent biopsies of accessible metastatic lesions.

• Patient Recruitment: Patients provided informed consent to receive 2-4 biopsies from metastatic sites. Inclusion criteria included a confirmed diagnosis of mCRC, while patients with contraindications to biopsy were excluded.

• Organoid Culture: Biopsies were processed and embedded in Matrigel, followed by cultivation in a growth medium optimized for tumor cell proliferation. Fresh medium was added every 2-3 days, and organoids were passaged every 7-10 days.

• Genetic Analysis: DNA was isolated from both organoid cultures and corresponding tumor biopsies. Genetic profiling was performed using SOLiD sequencing targeting 1,977 cancer-relevant genes. DNA copy number profiles were generated using CopywriteR.

• Statistical Analysis: The correlation between genetic profiles of organoids and their corresponding tumor biopsies was analyzed, focusing on somatic mutations and copy number variations.

Key Results and Findings

• Culture Success Rate: Organoids were successfully cultured from 10 out of 14 patients, resulting in a 71% success rate.

• Genetic Concordance: There was a high level of concordance in somatic mutations, with 90% of mutations shared between organoids and the original biopsies. The correlation coefficient for DNA copy number profiles was 0.89, indicating a strong similarity.

• Mutational Landscape: None of the mutations found exclusively in either the organoids or the biopsies were located in driver genes or genes relevant for drug targeting, suggesting that the discrepancies may be due to sampling variation or culture conditions.

Main Conclusion/Significance/Innovation

The study demonstrates that organoids derived from metastatic colorectal cancer biopsies can preserve the genetic diversity of the original tumors, supporting their potential use as an ex vivo platform for personalized cancer treatment. This could significantly enhance treatment decision-making by tailoring therapies to individual genetic profiles.

Research Limitations and Future Directions

• Limitations: The study acknowledges limitations related to the potential biological variability in tumor samples, the influence of low tumor cell percentages on genetic analysis, and the technical challenges in detecting mutations accurately.

• Future Directions: The authors recommend further clinical trials to validate the predictive value of organoids in treatment responses, which could pave the way for their integration into clinical practice for personalized oncology.

References

1. Genomic and transcriptomic plasticity in treatment-naive ovarian cancer. - Marlous Hoogstraat;Mirjam S de Pagter;Geert A Cirkel;Markus J van Roosmalen;Timothy T Harkins;Karen Duran;Jennifer Kreeftmeijer;Ivo Renkens;Petronella O Witteveen;Clarence C Lee;Isaac J Nijman;Tanisha Guy;Ruben van ’t Slot;Trudy N Jonges;Martijn P Lolkema;Marco J Koudijs;Ronald P Zweemer;Emile E Voest;Edwin Cuppen;Wigard P Kloosterman - Genome research (2014)
2. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. - Wouter R Karthaus;Phillip J Iaquinta;Jarno Drost;Ana Gracanin;Ruben van Boxtel;John Wongvipat;Catherine M Dowling;Dong Gao;Harry Begthel;Norman Sachs;Robert G J Vries;Edwin Cuppen;Yu Chen;Charles L Sawyers;Hans C Clevers - Cell (2014)
3. Organoid cultures derived from patients with advanced prostate cancer. - Dong Gao;Ian Vela;Andrea Sboner;Phillip J Iaquinta;Wouter R Karthaus;Anuradha Gopalan;Catherine Dowling;Jackline N Wanjala;Eva A Undvall;Vivek K Arora;John Wongvipat;Myriam Kossai;Sinan Ramazanoglu;Luendreo P Barboza;Wei Di;Zhen Cao;Qi Fan Zhang;Inna Sirota;Leili Ran;Theresa Y MacDonald;Himisha Beltran;Juan-Miguel Mosquera;Karim A Touijer;Peter T Scardino;Vincent P Laudone;Kristen R Curtis;Dana E Rathkopf;Michael J Morris;Daniel C Danila;Susan F Slovin;Stephen B Solomon;James A Eastham;Ping Chi;Brett Carver;Mark A Rubin;Howard I Scher;Hans Clevers;Charles L Sawyers;Yu Chen - Cell (2014)
4. CopywriteR: DNA copy number detection from off-target sequence data. - Thomas Kuilman;Arno Velds;Kristel Kemper;Marco Ranzani;Lorenzo Bombardelli;Marlous Hoogstraat;Ekaterina Nevedomskaya;Guotai Xu;Julian de Ruiter;Martijn P Lolkema;Bauke Ylstra;Jos Jonkers;Sven Rottenberg;Lodewyk F Wessels;David J Adams;Daniel S Peeper;Oscar Krijgsman - Genome biology (2015)
5. Prospective derivation of a living organoid biobank of colorectal cancer patients. - Marc van de Wetering;Hayley E Francies;Joshua M Francis;Gergana Bounova;Francesco Iorio;Apollo Pronk;Winan van Houdt;Joost van Gorp;Amaro Taylor-Weiner;Lennart Kester;Anne McLaren-Douglas;Joyce Blokker;Sridevi Jaksani;Sina Bartfeld;Richard Volckman;Peter van Sluis;Vivian S W Li;Sara Seepo;Chandra Sekhar Pedamallu;Kristian Cibulskis;Scott L Carter;Aaron McKenna;Michael S Lawrence;Lee Lichtenstein;Chip Stewart;Jan Koster;Rogier Versteeg;Alexander van Oudenaarden;Julio Saez-Rodriguez;Robert G J Vries;Gad Getz;Lodewyk Wessels;Michael R Stratton;Ultan McDermott;Matthew Meyerson;Mathew J Garnett;Hans Clevers - Cell (2015)
6. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. - Toshiro Sato;Daniel E Stange;Marc Ferrante;Robert G J Vries;Johan H Van Es;Stieneke Van den Brink;Winan J Van Houdt;Apollo Pronk;Joost Van Gorp;Peter D Siersema;Hans Clevers - Gastroenterology (2011)
7. Multiplexed array-based and in-solution genomic enrichment for flexible and cost-effective targeted next-generation sequencing. - Magdalena Harakalova;Michal Mokry;Barbara Hrdlickova;Ivo Renkens;Karen Duran;Henk van Roekel;Nico Lansu;Mark van Roosmalen;Ewart de Bruijn;Isaac J Nijman;Wigard P Kloosterman;Edwin Cuppen - Nature protocols (2011)
8. Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. - Joost S Vermaat;Isaac J Nijman;Marco J Koudijs;Frank L Gerritse;Stefan J Scherer;Michal Mokry;Wijnand M Roessingh;Nico Lansu;Ewart de Bruijn;Richard van Hillegersberg;Paul J van Diest;Edwin Cuppen;Emile E Voest - Clinical cancer research : an official journal of the American Association for Cancer Research (2012)
9. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. - Meritxell Huch;Craig Dorrell;Sylvia F Boj;Johan H van Es;Vivian S W Li;Marc van de Wetering;Toshiro Sato;Karien Hamer;Nobuo Sasaki;Milton J Finegold;Annelise Haft;Robert G Vries;Markus Grompe;Hans Clevers - Nature (2013)
10. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. - Meritxell Huch;Paola Bonfanti;Sylvia F Boj;Toshiro Sato;Cindy J M Loomans;Marc van de Wetering;Mozhdeh Sojoodi;Vivian S W Li;Jurian Schuijers;Ana Gracanin;Femke Ringnalda;Harry Begthel;Karien Hamer;Joyce Mulder;Johan H van Es;Eelco de Koning;Robert G J Vries;Harry Heimberg;Hans Clevers - The EMBO journal (2013)

Literatures Citing This Work

1. Modeling pancreatic cancer with organoids. - Lindsey A Baker;Hervé Tiriac;Hans Clevers;David A Tuveson - Trends in cancer (2016)
2. Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins. - Amanda M Pattison;Erik S Blomain;Dante J Merlino;Fang Wang;Mary Ann S Crissey;Crystal L Kraft;Jeff A Rappaport;Adam E Snook;John P Lynch;Scott A Waldman - Infection and immunity (2016)
3. Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition. - Martijn A J Koppens;Gergana Bounova;Paulien Cornelissen-Steijger;Nienke de Vries;Owen J Sansom;Lodewyk F A Wessels;Maarten van Lohuizen - Oncotarget (2016)
4. Heralding a new paradigm in 3D tumor modeling. - Eliza L S Fong;Daniel A Harrington;Mary C Farach-Carson;Hanry Yu - Biomaterials (2016)
5. Individual patient oesophageal cancer 3D models for tailored treatment. - John H Saunders;David Onion;Pamela Collier;Matthew S Dorrington;Richard H Argent;Philip A Clarke;Alex M Reece-Smith;Simon L Parsons;Anna M Grabowska - Oncotarget (2017)
6. Functional exploration of colorectal cancer genomes using Drosophila. - Erdem Bangi;Claudio Murgia;Alexander G S Teague;Owen J Sansom;Ross L Cagan - Nature communications (2016)
7. From tumour heterogeneity to advances in precision treatment of colorectal cancer. - Cornelis J A Punt;Miriam Koopman;Louis Vermeulen - Nature reviews. Clinical oncology (2017)
8. Interrogating open issues in cancer precision medicine with patient-derived xenografts. - Annette T Byrne;Denis G Alférez;Frédéric Amant;Daniela Annibali;Joaquín Arribas;Andrew V Biankin;Alejandra Bruna;Eva Budinská;Carlos Caldas;David K Chang;Robert B Clarke;Hans Clevers;George Coukos;Virginie Dangles-Marie;S Gail Eckhardt;Eva Gonzalez-Suarez;Els Hermans;Manuel Hidalgo;Monika A Jarzabek;Steven de Jong;Jos Jonkers;Kristel Kemper;Luisa Lanfrancone;Gunhild Mari Mælandsmo;Elisabetta Marangoni;Jean-Christophe Marine;Enzo Medico;Jens Henrik Norum;Héctor G Palmer;Daniel S Peeper;Pier Giuseppe Pelicci;Alejandro Piris-Gimenez;Sergio Roman-Roman;Oscar M Rueda;Joan Seoane;Violeta Serra;Laura Soucek;Dominique Vanhecke;Alberto Villanueva;Emilie Vinolo;Andrea Bertotti;Livio Trusolino - Nature reviews. Cancer (2017)
9. Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations. - Tyler M Foley;Susan N Payne;Cheri A Pasch;Alex E Yueh;Dana R Van De Hey;Demetra P Korkos;Linda Clipson;Molly E Maher;Kristina A Matkowskyj;Michael A Newton;Dustin A Deming - Molecular cancer research : MCR (2017)
10. The role of the microbiome in cancer development and therapy. - Aadra P Bhatt;Matthew R Redinbo;Scott J Bultman - CA: a cancer journal for clinicians (2017)

… (260 more literatures)

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