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

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.

Spatial Probabilistic Mapping of Metabolite Ensembles in Mass Spectrometry Imaging

“…Even more far-reaching than single molecule MPMs, data-integrating probability maps of entire lipid classes in SwissLipids (https://www.swisslipids.org) 15 , of large groups of molecules such as potassium adducts of lipids 10,16 or of any other user-defined set of metabolites, so called collective-projection probability maps (CPPM), pave the way for visualization and exploration of integrated MSI data: Here, molecular ensembles are transformed to their respective SPP representations, then collectively projected into a single image space (Fig. 2A), and finally subjected to spatial probabilistic mapping into CPPMs (Fig.…”

“…They generally enable new types of arithmetic operations with data, e.g., analysis of localized events and advanced statistical and homogeneity analysis of spatial data 8 . To this end, moleculaR provides the scientific community with solutions for molecular spatial probability mapping and for collective visualization and analysis of molecular ensembles, e.g., alkali metal adducts as ion milieu indicators 10 , energy charge as correlate of metabolic hotspots or entire lipid classes as the basis for the analysis of metabolic pathways.…”

The Ion Channel Gene KCNAB2 Is Associated with Poor Prognosis and Loss of Immune Infiltration in Lung Adenocarcinoma

“…It also encodes an aldo-keto reductase and negatively regulates members of the voltage-gated potassium channel family [ 20 ]. Some studies have found that KCNAB2 may be involved in the occurrence and development of lymphoma [ 21 ], colorectal cancer [ 22 ], pituitary tumor [ 23 ], and neuroblastoma [ 24 ], but its role in lung adenocarcinoma remains unknown.…”

Ceramide Transfer Protein (CERT): An Overlooked Molecular Player in Cancer

“…Meanwhile, the circulating lipids represent dietary nutrient intake and impacts, regulate hormonal and immunological responses and convey interorgan communications in cancer [4,5]. With the development of high throughput lipidomics and mass-spectrometry-based lipid imaging, an exponentially increased number of cancer-related lipid changes have been identified in cancer cells, animal models and clinical cohorts [6][7][8][9]. These often uncover previously overlooked lipid species in cancer, which offer new avenues for cancer diagnosis and treatment [6,8].…”