The brave new world of tumor organoids
Tumor organoids, as the name suggests, are 3-D mini-tumors that can be grown from tumor cells in the laboratory. The last few years have seen huge advances in organoid growing technologies and tumor organoids have been grown from a variety of different cancers, including colorectal, gastrointestinal, pancreatic, prostate, breast and liver cancers. Tumor organoids have been found to be genetically stable when grown in the laboratory and also match the molecular characteristics of the tumors that they were derived from. Importantly, tumor organoids can be actually grown from the cells of cancer patients that are collected during routine biopsies. Indeed, tumor organoids can be grown from cells obtained from a single cancer patient – which means that a tumor organoid could theoretically be generated from each individual patient. Progress in sequencing technologies has also meant that tumor organoids can be analyzed and sequenced rapidly, providing additional clues about tumor mutations, which could help in deciding which cancer drug might work best. Rapid advances in the gene editing CRISPR/Cas9 technologies has also meant that modifying organoids at the genetic level is now significantly easier. In a proof-of-concept study last year, Dr. Hans Clevers, a pioneer in this field, and his group at the Hubrecht Institute in the Netherlands, used CRISPR-Cas9 to modify human colon organoids. They deleted key DNA repair enzymes in the organoids, resulting in DNA repair deficiencies, which led to the development of mutations in the organoids over time. Interestingly, when these organoid mutations were sequenced, they matched signature mutation profiles, previously observed in colorectal cancers. Organoids could thus also help unravel the molecular origins of cancer in a systematic and step-wise manner.
A recent breakthrough study on the utility of tumor organoids by Dr. Nicola Valeri and his group at the Institute of Cancer Research in London, England, is especially exciting. Using 110 fresh biopsies from 71 patients with metastatic gastrointestinal cancer, they were able to grow patient derived organoids from ~70% of the biopsies, in the lab. Many of these tumor organoids had been derived from cancer patients who had already undergone many different cancer treatments and their tumors had grown refractory to many conventional therapies. This provided a unique opportunity, as researchers could test whether treatments that had failed in the cancer patients would also fail on the matched tumor organoids and conversely, if treatments that worked on the tumor organoids would work in the cancer patients as well. Researchers found that drugs that did not work on the tumor organoids, did not work in the patients either, 100% of the time and that drugs that worked on the tumor organoids worked in patients, 88% of the time. Researchers also subjected the patient derived tumors to extensive molecular characterization, profiling several cancer-related genes and found that there was a 96% match between the mutations found in the tumor organoids and the original tumors from which they were derived. Together these findings provided compelling evidence of the important predictive value of tumor organoids and could lead to a new era of personalized medicine where individual tumor treatment responses could be tested on custom organoids in the lab, before trying them out in cancer patients. Indeed, several research institutions have now started building “living biobanks” or collections of tumor organoids derived from actual cancer patients for carrying out high-throughput drug screening and potentially furthering personalized therapies. In conclusion, tumor organoids provide an extremely attractive and relevant system, both for developing and testing cancer treatments and that can be rapidly translated to the clinic and for understanding cancer related changes at a molecular level. To read a comprehensive and timely overview of the tumor organoid field, please click here.