Tumor-associated astrocytes promote tumor progression of Sonic Hedgehog medulloblastoma by secreting lipocalin-2

Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor-associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive. Here, we illuminated that TAAs showed a specific and dynamic pattern during SHH-MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early-stage tumors. We further demonstrated that lipocalin-2 (LCN2) secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 and AAV-Lcn2 shRNA, respectively, in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. In summary, we for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs.

 

Comments:

The passage you've provided discusses research findings related to Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) and the role of the tumor microenvironment (TME) in tumor progression and therapeutic resistance. Here's a breakdown of the key points in this research:

1. **SHH Subgroup of Medulloblastoma (MB):** This subgroup accounts for about 25% of all subgroups of MB. Medulloblastoma is a type of brain tumor, and the SHH subgroup refers to a specific molecular subtype within this cancer.

2. **Tumor Microenvironment (TME):** The TME refers to the cellular environment surrounding a tumor, including the surrounding cells, blood vessels, and extracellular matrix. It is known to play a crucial role in tumor progression and response to therapy.

3. **Tumor-Associated Astrocytes (TAAs):** These are astrocytes, a type of brain cell, that are found in the vicinity of the tumor. The passage suggests that TAAs can be reshaped in a way that promotes tumor progression through paracrine signaling, which involves the exchange of signals between nearby cells.

4. **Dynamic TAA Distribution:** The passage notes that TAAs exhibit a specific and dynamic pattern during the development of SHH-MB. In early-stage tumors, TAAs are not evenly distributed but tend to gather at the tumor margin as the tumor progresses.

5. **Lipocalin-2 (LCN2) Secretion:** TAAs secrete a protein called lipocalin-2 (LCN2), and this secretion is associated with promoting tumor growth. High levels of LCN2 are correlated with poor prognosis in MB patients.

6. **Effects of LCN2 on MB Cells:** In vitro experiments showed that knocking down LCN2 in TAAs inhibited the proliferation and migration abilities of MB cells, suggesting that LCN2 is involved in promoting these cancer cell behaviors.

7. **STAT3 Signaling Pathway:** TAAs are shown to accelerate tumor growth by secreting LCN2, and this effect is mediated through the STAT3 signaling pathway. STAT3 is a protein that plays a role in regulating various cellular processes, including cell growth and survival.

8. **Therapeutic Strategies:** The research suggests that targeting the STAT3 signaling pathway, either with an inhibitor called WP1066 or with AAV-Lcn2 shRNA (a genetic tool to silence LCN2), in TAAs can counteract the effects of LCN2 on tumor progression. This indicates a potential therapeutic strategy for SHH-MB by targeting TAAs.

9. **Prognostic Value:** The study highlights that LCN2 has potential prognostic value, meaning it could be used as a marker to predict the outcome of MB patients.

In summary, this research sheds light on the role of TME, specifically TAAs and LCN2, in promoting the progression of SHH-MB. It also proposes potential therapeutic avenues for targeting TAAs and the STAT3 pathway to combat this type of brain tumor.

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