Wiregrass Propagation at the Andrews Nursery in Florida

Abstract

<h3>ABSTRACT</h3> Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant metabolism and subsequent signaling of hyaluronan (HA). Hyaluronan Mediated Motility Receptor (RHAMM, <i>HMMR</i>) is a HA receptor that enables tumor cells to sense and respond to the TME during breast cancer progression. Focused gene expression analysis of an internal breast cancer patient cohort demonstrates increased <i>RHAMM</i> expression correlates with aggressive clinicopathological features. We also develop a 27-gene RHAMM-dependent signature (RDS) by intersecting differentially expressed genes in lymph node positive cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validate in an independent cohort. We demonstrate RDS predicts for poor survival and associates with invasive pathways. Further analyses using CRISPR/Cas9 generated <i>RHAMM</i> -/- breast cancer cells provide direct evidence that RHAMM promotes invasion <i>in vitro</i> and <i>in vivo</i>. Additional immunohistochemistry studies highlight heterogeneous RHAMM expression, and spatial transcriptomics confirms the RDS emanates from RHAMM-high invasive niches. We conclude RHAMM upregulation leads to the formation of ‘invasive niches’, which are enriched in RDS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes.