Ricci, A. A. | bioRxiv Science

bioRxiv2025

The Pervasive Negative Regulation of Ion Channel Functional Families Across Human Cancers

The transmembrane transport of molecules and ions is fundamental to cellular homeostasis and coordination of physiological processes. During tumorigenesis, these processes undergo significant alterations in response to oncogenic transformations and microenvironmental pressures. However, a comprehensive systems-level characterization of transportome alterations across cancer types has been lacking. Here, we integrate structural, functional, and mechanistic annotations of all known human Ion Channels and Transporters (ICTs) into a curated database, organizing them into biologically coherent gene sets based on shared physiological and biophysical properties such as permeant species, gating mechanism, and transport directionality. By leveraging Gene Set Enrichment Analysis (GSEA) across transcriptomic profiles from 19 tumor types, we reveal a recurrent downregulation of ICTs--particularly ion channels--accompanied by selective upregulation of specific pump classes. Our findings uncover a conserved signature of transportome reprogramming in cancer and provide a quantitative framework for future integrative studies of ICT function. This work highlights both the complexity and plasticity of cellular transport systems in oncogenesis and offers a resource for modeling their roles in cancer systems biology.

cancer biology↗

bioRxiv2023

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Brain metastasis (BM) is a dire prognosis across cancer types. It is largely unknown why some tumors metastasize to the brain whereas others do not. We analyzed genomic and transcriptional data from clinical samples of breast cancer BM (BCBM) and found that nearly all of them carried p53-inactivating genetic alterations through mutations, copy-number loss, or both. Importantly, p53 pathway activity was already perturbed in primary tumors giving rise to BCBM, often by loss of the entire 17p chromosome-arm. This association was recapitulated across other carcinomas. Experimentally, p53 knockout was sufficient to drastically increase BCBM formation and growth in vivo, providing a causal link between p53 inactivation and brain tropism. Mechanistically, p53-deficient BC cells exhibited altered lipid metabolism, particularly increased fatty acid (FA) synthesis and uptake, which are characteristic of brain-metastasizing cancer cells. FA metabolism was further enhanced by astrocytes in a p53-dependent manner, as astrocyte-conditioned medium increased FASN, SCD1, and CD36 expression and activity, and enhanced the survival, proliferation and migration of p53-deficient cancer cells. Consequently, these cells were more sensitive than p53-competent cells to FA synthesis inhibitors, in isogenic cell cultures, in BCBM-derived spheroids, and across dozens of BC cell lines. Lastly, a significant association was observed between p53 inactivation, astrocyte infiltration, and SCD1 expression in clinical human BCBM samples. In summary, our study identifies p53 inactivation as a driver of BCBM and potentially of BM in general; suggests a p53-dependent effect of astrocytes on BC cell behavior; and reveals FA metabolism as an underlying, therapeutically-targetable molecular mechanism.

cancer biology↗