Abstract
Scientists have for the first time grown “organoids” from human prostate tumor biopsies in the lab and have correlated their genetic mutations with response to various drugs. Researchers hope the findings lead to better prostate cancer models and more-personalized treatment.
Prostate cancer is notoriously difficult to culture in the lab, and many of the gene alterations that are instrumental in its growth are not represented in the few prostate cancer cell lines currently available.
Scientists have now for the first time grown “organoids,” tiny 3-dimensional (3-D) structures composed of thousands of cells grouped together and arranged like an organ or tissue, from human prostate tumor biopsies. They have also correlated genetic mutations in the models with their response to various drugs (Cell 2014;159:176–87). A companion paper describes how to create healthy prostate organoids (Cell 2014;159:163–75).
“This is a notable breakthrough for the prostate cancer field,” says David Tuveson, MD, PhD, director of the Lustgarten Foundation Pancreatic Cancer Research Laboratory at Cold Spring Harbor Laboratory in New York, who was not involved in the study but is trying to grow organoids derived from pancreatic tumor samples. “This is the first system where you're able to study the biology of prostate cancer in a much more representative setting.”
The clinical implications are profound, Tuveson adds, because prostate cancer is the most common cancer among American men.
In the new study, researchers used a 3-D culture method to grow six prostate cancer organoids derived from biopsies of patients with metastatic prostate cancer. A seventh organoid grew from a patient's circulating tumor cells. RNA sequencing revealed each organoid was molecularly similar to the metastasis from which it came.
According to the study's senior author, Yu Chen, MD, PhD, tumor organoids are not the same as benign organoids, in which multiple cell types mimic the normal organ. “In cancer, the organoid cells are more homogeneous,” says Chen, a physician-scientist in the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center in New York, NY.
Even so, each prostate cancer organoid was distinct from the others, containing unique mutations from each patient's tumor. Whole-exome sequencing revealed alterations such as TMPRSS2–ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. “These mutations are prostate cancer–specific, so there is a need for in vitro prostate cancer models to study them,” says Chen.
Stained pathology slides of a prostate cancer patient's biopsy specimen (left) and of an organoid made from that tumor specimen.
Stained pathology slides of a prostate cancer patient's biopsy specimen (left) and of an organoid made from that tumor specimen.
Researchers used the organoids to test several approved and experimental prostate cancer therapies. The androgen receptor–amplified MSK-PCa2 organoid line, for example, was extremely sensitive to enzalutamide (Xtandi; Astellas Pharma) both in vitro and in vivo, whereas several other organoid lines were resistant.
Chen's team is now growing more organoids from patients with advanced prostate cancer. They plan to start large-scale in vitro testing to determine which drugs work best in different subgroups of patients.
“If we can identify molecular determinants of drug sensitivity and resistance, we can design more targeted clinical trials,” Chen says. The long-term goal, he adds, is to optimize treatment by developing prostate cancer organoids derived from each patient's tumor and testing drugs on the organoid before they are given to the patient.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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