Transcriptomic intratumor heterogeneity of breast cancer patient-derived organoids may reflect the unique biological features of the tumor of origin

Abstract

Background The intratumor heterogeneity (ITH) of cancer cells plays an important role in breast cancer resistance and recurrence. To develop better therapeutic strategies, it is necessary to understand the molecular mechanisms underlying ITH and their functional significance. Patient-derived organoids (PDOs) have recently been utilized in cancer research. They can also be used to study ITH as cancer cell diversity is thought to be maintained within the organoid line. However, no reports investigated intratumor transcriptomic heterogeneity in organoids derived from patients with breast cancer. This study aimed to investigate transcriptomic ITH in breast cancer PDOs. Methods We established PDO lines from ten patients with breast cancer and performed single-cell transcriptomic analysis. First, we clustered cancer cells for each PDO using the Seurat package. Then, we defined and compared the cluster-specific gene signature (ClustGS) corresponding to each cell cluster in each PDO. Results Cancer cells were clustered into 3–6 cell populations with distinct cellular states in each PDO line. We identified 38 clusters with ClustGS in 10 PDO lines and used Jaccard similarity index to compare the similarity of these signatures. We found that 29 signatures could be categorized into 7 shared meta-ClustGSs, such as those related to the cell cycle or epithelial–mesenchymal transition, and 9 signatures were unique to single PDO lines. These unique cell populations appeared to represent the characteristics of the original tumors derived from patients. Conclusions We confirmed the existence of transcriptomic ITH in breast cancer PDOs. Some cellular states were commonly observed in multiple PDOs, whereas others were specific to single PDO lines. The combination of these shared and unique cellular states formed the ITH of each PDO.

Establishment of patient‐derived organoids for guiding personalized therapies in breast cancer patients

“…This suggests a higher success rate than previously reported 15 . As previously reported, tumors with high proliferative potential, such as a higher nuclear grade and Ki‐67 index, were more likely to be successfully established 17,19 . However, we found that no noticeable dissimilarity was present among distinct grades or different Ki‐67 index cohorts.…”

“…15 As previously reported, tumors with high proliferative potential, such as a higher nuclear grade and Ki-67 index, were more likely to be successfully established. 17,19 However, we found that no noticeable dissimilarity was present among distinct grades or different Ki-67 index cohorts. It is possible that a greater percentage of chemotherapy treatment was frequently associated with higher Ki-67 index groups.…”

Patient-derived organoids: a promising tool for breast cancer research

“…This suggests that PDO-specific cell clusters reflect different PDO properties. Moreover, they subjected two other BC tissues or PDO pairs to RNA-seq and revealed that although a complete one-to-one correspondence was not achieved, PDOs retained some degree of tumor heterogeneity of the original tissue after successive passages (40).…”

Dynamic culture system advances the applications of breast cancer organoids for precision medicine

“…The smaller initial sample, which is hard to expand quickly enough to meet the cell amount required for drug sensitivity analysis, will also prolong the detection cycle. Breast cancer samples also face the same situation, clinicians prefer the less invasive puncture biopsy method for sampling (11,12) . Usually, the puncture tissue can obtain less tumor cells, which will directly lead to the extension of the organoid culture cycle in the existing organoid culture system, and it is di cult to provide timely diagnosis and treatment suggestions for patients.…”