Eric Rahrmann

There are 611,720 cancer-related deaths projected to occur in the U.S. in 2024. The majority of cancer-related deaths are a result of metastasis, a process where cancer cells spread from the primary tumor to other organs in the body. Despite a wealth of studies over decades, this process remains poorly understood and resistant to treatment.

Metastasis has been assumed to be an abnormal process mediated by primary cancers. However, this group's groundbreaking work is the first to divorce metastasis from upstream tumorigenesis and link it to a novel physiologic process, which is central to the maintenance of normal tissues, uncovering a completely new paradigm for metastasis. Specifically, the PI identified the Sodium Leak Channel Non-Selective Protein (NALCN) as a key regulator of epithelial cell trafficking, both normal and malignant tissues, unmasking this cascade as a cancer-independent phenomenon and a novel therapeutic target. These findings, published in 2022, will allow refinement of the current model of metastasis and have unmasked a potential novel target for anti-metastatic therapies. There are, however, several outstanding questions revolving around both the understanding of the biochemical and cellular mechanisms involved in NALCN-regulated cell dissemination and if these findings extend more broadly to other cancer types. The initial findings focused on mouse models of gastric, intestinal, and pancreatic adenocarcinomas and were based on evidence of significant enrichment of NALCN mutations in human gastrointestinal cancers. Preliminary analysis of human cancers that commonly metastasize, but lack enrichment of NALCN nonsynonymous mutations, has identified that reduced NALCN copy number (heterozygous and homozygous deletion, GISTIC scores) is associated with more aggressive breast adenocarcinomas and metastasis to intraperitoneal organs. The central hypothesis is that ion channels regulate normal mammary gland and breast adenocarcinoma plasticity and cell dissemination by altering membrane potential, which can be leveraged for the development of effective therapies. Understanding this process of cell plasticity and dissemination not only creates a platform for identifying new anti-metastatic drugs in cancer models but could also be leveraged in normality for tissue repair and regenerative medicine.