Adaptation of colon cancer cells to the brain microenvironment: the role of IRS2

Brain metastases (BMs) from colorectal cancer (CRC) are the fourths leading cause of BMs, and their incidence is on the rise. Yet, mechanisms mediating the formation of BMs by CRC cells are unknown. We aimed to explore genomic drivers enabling tropism and adaptation of CRC cells to the brain environment and decipher mechanisms enabling the process.

We analyzed FoundationOne database, which contains genomic alterations data of cancer-related genes, in 148 CRC BMs and 4292 CRC liver metastases (LMs). Increased prevalence of genomic alterations was noted in several genes, among them insulin receptor substrate 2 (IRS2) gene, that was amplified in 13% of BMs samples, compared to only 3% of LMs (p<0.0001). IRS2 is a cytoplasmic signaling molecule mediating effects of insulin and IGF-1 by acting as an adaptor between their receptors and downstream effectors.

Importantly, immunohistochemistry of human clinical samples showed increased expression of IRS2 in BMs compared to LMs.

IRS2-overexpressed CRC cells had increased proliferation, migration, and colony formation capacity, while IRS2-silenced CRC cells had reduced proliferation.

Furthermore, activated-human astrocytes conditioned media (aHA-CM) or HA were used to create an in-vitro system mimicking the brain environment. IRS2-overexpressed CRC cells survived better in aHA-CM and had enhanced 3D sphere formation in co-culture with HA whereas IRS2-silenced CRC cells survived less in aHA-CM.

Finally, using intracranial CRC BMs mouse model, we observed elevated expression of IRS2 following the development of BMs.

These data indicate a role for genomic alterations, specifically IRS2 amplification, in promoting the formation of BMs in CRC.