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Organoids: The Future of Personalized Cancer Therapy
- Noya Bar-Nathan
- 8 hours ago
- 5 min read
This blog post serves to simplify the scholarly article by Sebastien Taurin and colleagues on "Patient-derived tumor organoids: A preclinical platform for personalized cancer therapy".
Introduction:
Every year, millions of people receive chemotherapy, not knowing if it will be successful in getting rid of their cancer or not. It puts them in a very scary position, having to go through something so exhausting without knowing if it's worth it or not. Even when tumors share the same genetic mutation, responses to treatment can vary widely because cancer is highly complex and diverse. If only there were a way to better be able to predict the response by creating a more personalized plan for an individual person… That's where Organoids come in!
Current personalized cancer treatments are often expensive and inefficient. Many approaches fail to accurately predict how a patient’s tumor will respond, leading to trial-and-error treatment decisions. Researchers have tried using 2D cancer cell lines, which are cheap and easy to use, but they are unrealistic because they do not reflect the true structure of a patient’s tumor. Animal models have also been used, where tumors are implanted into mice. While this approach is more representative of real tumors, it is slower and more expensive. Additionally, mice are biologically different from humans, which can limit how useful the results are. Lastly, testing tumor genomics helps identify mutations, but it does not reveal how the tumor will actually respond to a drug.
With this, patient-derived tumor organoids attempt to bridge the gap to personalized treatments that are still in reach for most patients.
The Research:
To put simply, the study asks if Patient- Derived Tumor Organoids (PDTOs) can be used reliably to predict how a cancer patient will respond to drug treatment in order to advance the cancer research field.
PDTOs are a three-dimensional cluster of cells that have grown from stem cells. Stem cells are unique, undifferentiated (don’t have a particular function) cells that are capable of differentiating into specialized cell types, which in this case are used to resemble miniature organs. These cells are taken from a small piece of the patient's cancerous tissue, making the miniature organ completely personalized to the patient. This mini organ keeps the genetic mutation, protein expression (controls the overall structure and chemical singling), consistent with the patient's actual organ, allowing scientists to see how a patient would react to a drug administered to them. So instead of drugs being tested on random cells, they get to be tested on YOUR tumor, which is a HUGE advantage for cancer research!
This is a review paper, which means that the authors analyzed results from several previous studies instead of just focusing on one experiment. This allows us to see and learn more about PDTOs through various methods. These different methods are used to validate how accurate and reliable these organoids are.
Organoid Culture Techniques (3D tumor growth) + Drug Sensitivity Testing
This method is the basis of all the other techniques, as it is how the organoids are specifically grown. In this method, researchers take tumor samples from patients and grow them in a special 3D gel called Matrigel that promotes cell growth. This allows the cell cultures to grow in 3D, creating more similarity to the real cancer patient’s tumor. After these cultures are grown, scientists can expose them to different treatments like chemotherapy, radiation, and targeted therapy to see how the tumor would respond and determine if they need to keep or modify the patient’s treatment plan.
This method seemed to show a high success rate of 60–90 percent in establishment (growing a successful organoid that can be maintained). The success rate differs depending on the cancer type but generally shows similar growth patterns to the original tumor. This approach also appears to be highly effective in predicting treatment response, with some cancers showing a predictive accuracy above 90 percent. However, immune therapies were more difficult to test since the necessary immune cells were not fully present in organoids.
However, some cancers had lower establishment success rates, such as prostate cancer at 15–30 percent, and some lung cancers at 20–40 percent, showing areas for improvement. In addition, some long-term cultures experienced genetic drift, where the cells slowly changed over time and became more different from the original tumor, making this method less reliable for extended studies. Regardless, this method paved the way for much of the research that uses PDTOs.
Genomic and Molecular Analysis (DNA & Protein Testing)
This next method was used to validate the accuracy of the organoids by seeing how similar the genetic material of the PDTO was to the actual tumor. Researchers used the following techniques to see if the organoids mutations or protein markers (specific proteins used to recognize the tumor characteristics) were different, which affects the organoids reliability in predicting how a patient will react to treatment.
DNA sequencing- reading the exact order of nucleotides to compare between the actual tumor that the patient has and the organoid.
Copy number variation analysis- a test that checks if DNA regions were deleted or duplicated compared to the original cell
Immunohistochemistry- a method that uses color staining and antibodies (proteins that fight foreign substances) to detect certain proteins inside the organoid cells
Single-cell RNA sequencing- analyzing gene activity in individual cells to see how different cells behave within the same tumor)
This was important to verify that the mutations looked the same in the organoid and the original tumor. For example, for breast cancer, the organoid would also need to have the same HER2 mutation and the ER receptor in order to make the conditions of the organoid similar to the real tumor.
Overall, this was very effective as results showed high genetic similarity between organoids and original tumors and served as an accurate representation to the patient's tumor. Most driver mutations were preserved.
CRISPR Gene Editing
Lastly, in order to add specific mutations like KRAS, which drives cancer growth, and remove tumor suppressor genes (such as p53, which regulates cell division), some researchers use the CRISPR-Cas9 system. This system works by designing a short piece of RNA to guide CRISPR to a target. The CRISPR-Cas9 system is then delivered into organoid cells in the lab using modified, harmless viruses that act as carriers. The Cas9 enzyme cuts the DNA at the targeted location based on the RNA sequence, allowing the gene to be disabled (knockout) or a new mutation to be inserted (knock-in). This enables scientists to measure growth rate, survival, and resistance patterns after drugs are administered.
Conclusion:
Overall, the research in this paper highlights the strong potential of PDTOs in personalized cancer therapy, as they are able to maintain key mutations and protein markers of the original tumor, helping to more accurately predict patient drug responses. However, it is important to note that this is not yet a perfect technique. Its reliability and accuracy still need to become more consistent across different cancer types; studies should include larger sample sizes, and methods must be developed to reduce genetic drift in long-term cell cultures to better replicate the tumor environment.
In the future, the authors highlight the importance of creating standardized protocols for establishing the organoids as well as having more large-scale trials to verify that it improves most patient outcomes. The development of organoid biobanks, which are large amounts of already made PDTO’s, would be helpful for this objective as it would allow scientists not to have to worry about culturing the PDTOs but studying specific rare cancers and more quickly comparing drug responses, which could help create new drugs in the future.
All in all, while there are still ways to grow with PDTOs, the overall progress in personalized cell therapy is very exciting and is something we should continue to follow in order to make the recovery process for patients as easy as possible!
