Biology subjects

Lind, D. E.

Publications and source records attributed to Lind, D. E..

3 recordsLinked to original sources

bioRxiv2025

ALK/ATR combination therapy is effective in neuroblastoma mouse tumors driven by MYCN

Summary paragraphOne of the key features of high-risk neuroblastoma (NB) is MYCN-amplification. While MYCN is still regarded as therapeutically challenging despite intensive efforts to find targeting compounds, inhibitors against Anaplastic Lymphoma Kinase (ALK) are now being evaluated among ALK-driven NB patients with promising results. There is a pressing need to find alternative treatment regimens for ALK naive MYCN-amplified patients, as current regimes are accompanied by significant mortality and morbidity. Here we show that genetically removing Alk in the Th-MYCN-driven engineered NB mouse model (GEMM) resulted in decreased tumor penetrance, and survival of Th-MYCN homozygote GEMMs, suggesting that Alk activity contributes to aggressiv e neuroblastoma development in this model. Given the high levels of replication stress induced in Th-MYCN tumors, we employed inhibitors of Ataxia Telangiectasia Rad3 related (ATR), combining ATR and ALK inhibition in a 14-day treatment regime, and comparing with ATR inhibitor monotreatment. Th-MYCN tumor bearing mice that received ATRi/ALKi combination treatment exhibited significantly increased survival compared to ATRi alone, that was sustained over time. Together, our data highlight a potentially effective treatment option for the currently challenging category of MYCN-amplified NB patients lacking ALK mutations.

cancer biology↗

bioRxiv2024

Spatial transcriptomics exploration of the primary neuroblastoma microenvironment unveils novel paracrine interactions

High-risk neuroblastomas exhibit a high degree of intratumoral heterogeneity. Single-cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial information about local signaling dynamics. To address this gap, we profiled untreated and chemotherapy-treated high-risk neuroblastomas from 2 patients using spatial transcriptomics. We confirmed the transcriptional and cellular heterogeneous nature of the neuroblastoma microenvironment and identified several unique spatial niches and patterns. In one of the treated tumors, a spatially constrained cluster of undifferentiated and 11p-gained cancer cells was identified, surrounded by a rim of macrophages. A signaling interaction between the chemokine CCL18 and its receptor PITPNM3 was predicted between these cells and we experimentally demonstrated that CCL18 increases neuroblastoma cell migration. In the other tumor, we identified a stromal cluster with high transcriptional similarity to the adrenal cortex. These adrenocortical-like cells expressed the ALK ligand ALKAL2 and were predicted to communicate with neighboring ALK expressing cancer cells. We demonstrated a unique developmental pattern of adrenal medulla-specific expression of ALK and adrenocortical-specific expression of ALKAL2, suggesting a role of these signaling interactions in neuroblastoma carcinogenesis.

cancer biology↗

bioRxiv2023

ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to ATR inhibition

High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and ALK, which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signalling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-day ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-day combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumour cells to a neuronal/Schwann cell lineage identity. Our results identify a unique ability of ATR inhibition to trigger neuroblastoma differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.

cancer biology↗