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RNAi screen identifies essential regulators of human brain metastasis-initiating cells
Mohini Singh1,2, Chitra Venugopal1,3, Tomas Tokar4
1MDCL 5027, Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
Abstract:
Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-β ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.
Insights
Researchers identified brain metastasis-initiating cells (BMICs) and developed a novel preclinical model. SPOCK1 was found to be a key regulator of brain metastasis initiation and progression, offering a potential therapeutic target.
Area of Science:
- Oncology
- Cancer Biology
- Translational Research
Background:
- Brain metastases (BM) are the most common brain tumors in adults and a major cause of cancer mortality.
- Current preclinical models inadequately represent the metastatic cascade, limiting research into BM and their treatment.
- There is a critical need for novel models and therapeutic targets for brain metastases.
Purpose of the Study:
- To establish a novel preclinical model for investigating human brain metastases.
- To identify key regulators of brain metastasis-initiating cells (BMICs).
- To explore potential therapeutic targets for blocking the metastatic process in brain metastases.
Main Methods:
- Identification of a unique subset of stem-like cells from human brain metastases, termed BMICs.
- Establishment of a BMIC patient-derived xenotransplantation (PDXT) model for in vitro and in vivo studies.
- RNA interference screens to identify essential BMIC regulators, including SPOCK1 and TWIST2.
- Analysis of SPOCK1 expression in primary lung cancer specimens and its correlation with BM development.
- Protein-protein interaction network mapping to identify novel pathway interactors.
Main Results:
- SPOCK1 and TWIST2 were identified as essential regulators of BMICs.
- SPOCK1 was confirmed as a novel regulator of BMIC self-renewal, tumor initiation, and lung-to-brain metastasis.
- SPOCK1 overexpression was specifically observed in lung cancer patients who developed brain metastases.
- Novel pathway interactors with prognostic value in lung cancer patients were identified.
- INHBA expression was reduced in BMICs with SPOCK1 knockdown.
Conclusions:
- A valuable preclinical model for brain metastases (BM) was developed.
- Novel regulators of BMICs, including SPOCK1, were identified.
- SPOCK1 represents a potential therapeutic target to inhibit brain metastasis.
- These findings offer a pathway to transform brain metastases from a fatal disease to a more treatable condition.
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