Neuroimaging and clinical features of bilateral Wallerian degeneration of middle cerebellar peduncles subsequent to pontine infarction.

OBJECTIVE: Wallerian degeneration (WD) of the middle cerebellar peduncles (MCPs) following pontine infarction is a rare secondary degenerative neurological condition. Due to its infrequency, there is limited research on its characteristics. METHODS: This study aims to present three cases of WD of MCPs following pontine infarction and to analyze the prognosis, clinical manifestations, and neuroimaging features by amalgamating our cases with previously reported ones. RESULTS: The cohort consisted of 25 cases, comprising 18 men and 7 women aged 29 to 77 years (mean age: 66.2 years). The majority of patients (94%) exhibit risk factors for cerebrovascular disease, with hypertension being the primary risk factor. Magnetic resonance imaging (MRI) can detect WD of MCPs within a range of 21 days to 12 months following pontine infarction. This degeneration is characterized by bilateral symmetric hyperintensities on T2/FLAIR-weighted images (WI) lesions in the MCPs. Moreover, restricted diffusion, with hyperintensity on diffusion-weighted imaging (DWI) and low apparent diffusion coefficient (ADC) signal intensity may be observed as early as 21 days after the infarction. Upon detection of WD, it was observed that 20 patients (80%) remained asymptomatic during subsequent clinic visits, while four (16%) experienced a worsening of pre-existing symptoms. CONCLUSIONS: These findings underscore the importance of neurologists enhancing their understanding of this condition by gaining fresh insights into the neuroimaging characteristics, clinical manifestations, and prognosis of individuals with WD of bilateral MCPs.

SCUBE2 mediates bone metastasis of luminal breast cancer by modulating immune-suppressive osteoblastic niches.

Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal breast cancer. The mechanisms of this subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog signaling with Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provide a mechanistic explanation for bone preference in luminal breast cancer metastasis and new approaches for metastasis treatment.

IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit ß (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB-expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB-targeting approaches for metastasis treatment.

Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation.

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1ß (IL-1ß) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1ß axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.