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

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.

Clinical and electrophysiological findings of facial palsy in a case of hereditary gelsolin amyloidosis.

Hereditary gelsolin amyloidosis (HGA) is an autosomal dominant systemic amyloidosis, characterized by cranial and sensory peripheral neuropathy, corneal lattice dystrophy, and cutis laxa. We report a case of HGA presenting with bilateral facial palsy. A 70-year-old Japanese man presented with slowly progressive bilateral facial palsy and facial twitching, which had started in his 40s. His mother also had the same symptoms due to an unknown cause but rest of the family did not. He showed incomplete facial palsy with no frontal muscle movement and partial movement of the orbicularis oris and orbicularis oculi muscles. The patient showed no synkinesis. Electroneurography revealed symmetric low compound motor action potential amplitude of the orbicularis oris muscle, and a nerve excitability test showed a symmetric increase in the response threshold. Despite the partial voluntary movement of the orbicularis oculi muscle, bilateral blink reflexes were absent. He also showed facial spasms after contraction of the orbicularis oris muscle. Genetic testing revealed a heterozygous c.640G>A mutation (p. Asp214Asn); therefore, the patient was diagnosed with HGA. HGA related facial palsy showed moderate bilateral, upper blanch-dominant axonal degeneration of the facial nerve without reinnervation, and trigeminal nerve neuropathy.