IRS2 as a driver of brain metastasis in colorectal cancer: A potential target for novel therapeutic strategies

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Inbal Greenberg 1 2, Fayhaa Khair 1 2, Keren Merenbakh-Lamin 1, Ethan Sokol 3, Anat Klein Goldberg 1, Dor Simkin 1, Avishay Spitzer 1, Moshe Benhamou 1, Shai Bar-Shira 1 2, Michal Raz 4, Rachel Grossman 2 5, Eilam Yeini 6, Paula Ofek 6, Tomer Meirson 7, Ronit Satchi-Fainaro 6 8, Hadas Reuveni 9 10, Tami Rubinek 1 2, Ido Wolf 1 2

 

1Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

2Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

3Foundation Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

4Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

5Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

6Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.

7Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.

8Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

9Purple Biotech Ltd. Science Park, Rehovot, Israel.

10TyrNovo Ltd. Science Park, Rehovot, Israel.

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Background

Colorectal cancer (CRC) ranks as the fourth most common cause of brain metastasis (BM), with its incidence on the rise. However, the molecular mechanisms driving the formation of these lesions from CRC remain unclear.

 

Methods

We analyzed the Foundation Medicine genomic database, which includes over 35,000 CRC samples from both local and metastatic sites. The role of insulin receptor substrate 2 (IRS2) in CRC brain tropism was investigated using various in vitro (co-culture systems and 3D sphere formation assays), in vivo (intracranial and subcutaneous mouse models), and ex vivo (CRC Patient-Derived Explants) models. The molecular and metabolic effects of IRS2 were examined through RNA sequencing and Seahorse analysis. The therapeutic potential of a combined treatment with NT219, an IRS2 inhibitor, and 5-fluorouracil (5-FU) was assessed using our CRC BM mouse model.

 

Results

Our research reveals a distinctive genomic profile of CRC BM and highlights the role of IRS2 in promoting CRC BM. IRS2 mediates its effect by modulating the β-catenin and oxidative phosphorylation (OXPHOS) pathways. We developed a mouse model of BM from CRC and demonstrated that treatment with the IRS2 inhibitor NT219, in combination with 5-FU, significantly suppresses BM development and prolongs survival.

 

Conclusions

Our work underscores the unique role of IRS2 in facilitating CRC brain adaptation and suggests a novel therapeutic strategy for CRC patients with BM.