A Drastic Shift in Lipid Adducts in Colon Cancer Detected by MALDI-IMS Exposes Alterations in Specific K(+) Channels

SIMPLE SUMMARY: Colorectal cancer (CRC) is one of the most preventable yet deadliest cancers, one reason being that it involves very different lesions. Currently, there is a great international effort to improve CRC classification using as many molecular features as possible. A cutting-edge technique, imaging mass spectrometry, is used to enable the visualization of the bidimensional (2D) distribution of molecules across tissues in order to study how the composition of the cell membrane, in particular membrane lipids, changes in tumors. Our previous studies indicate that lipid composition is highly sensitive to cell alterations. Importantly, during the analysis, we are also able to establish changes in charged lipids, observations that can be misinterpreted. A close study of our results alongside information from public databases leads to the identification of gene coding for a potassium channel that could account for our observations and could represent a suitable target for drug development. ABSTRACT: Even though colorectal cancer (CRC) is one of the most preventable cancers, it is one of the deadliest, and recent data show that the incidence in people <50 years has unexpectedly increased. While new techniques for CRC molecular classification are emerging, no molecular feature is as yet firmly associated with prognosis. Imaging mass spectrometry (IMS) lipidomic analyses have demonstrated the specificity of the lipid fingerprint in differentiating pathological from healthy tissues. During IMS lipidomic analysis, the formation of ionic adducts is common. Of particular interest is the [Na(+)]/[K(+)] adduct ratio, which already functions as a biomarker for homeostatic alterations. Herein, we show a drastic shift of the [Na(+)]/[K(+)] adduct ratio in adenomatous colon mucosa compared to healthy mucosa, suggesting a robust increase in K(+) levels. Interrogating public databases, a strong association was found between poor diagnosis and voltage-gated potassium channel subunit beta-2 (KCNAB2) overexpression. We found this overexpression in three CRC molecular subtypes defined by the CRC Subtyping Consortium, making KCNAB2 an interesting pharmacological target. Consistently, its pharmacological inhibition resulted in a dramatic halt in commercial CRC cell proliferation. Identification of potential pharmacologic targets using lipid adduct information emphasizes the great potential of IMS lipidomic techniques in the clinical field.