Receptor for hyaluronan-mediated motility (RHAMM) defines an invasive niche associated with tumor progression and predicts poor outcomes in breast cancer patients

Sarah E. Tarullo, Yuyu He, Claire Daughters, Todd P. Knutson, Christine M. Henzler, Matthew A. Price, Ryan Shanley, Patrice Witschen, Cornelia Tolg, Rachael E. Kaspar, Caroline Hallstrom, Lyubov Gittsovich, Megan L. Sulciner, Xihong Zhang, Colleen L. Forster, Carol A. Lange, Oleg Shats, Michelle Desler, Kenneth H. Cowan, Douglas YeeKathryn L. Schwertfeger, Eva A. Turley, James B. McCarthy, Andrew C. Nelson

Research output: Contribution to journalArticlepeer-review

Abstract

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 synthesis, processing, and signaling of hyaluronan (HA). Hyaluronan-mediated motility receptor (RHAMM, CD168; HMMR) is an HA receptor enabling tumor cells to sense and respond to this aberrant TME during breast cancer progression. Previous studies have associated RHAMM expression with breast tumor progression; however, cause and effect mechanisms are incompletely established. Focused gene expression analysis of an internal breast cancer patient cohort confirmed that increased RHAMM expression correlates with aggressive clinicopathological features. To probe mechanisms, we developed a novel 27-gene RHAMM-related signature (RRS) by intersecting differentially expressed genes in lymph node (LN)-positive patient cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validated in an independent cohort. We demonstrate that the RRS predicts for poor survival and is enriched for cell cycle and TME-interaction pathways. Further analyses using CRISPR/Cas9-generated RHAMM−/− breast cancer cells provided direct evidence that RHAMM promotes invasion in vitro and in vivo. Immunohistochemistry studies highlighted heterogeneous RHAMM protein expression, and spatial transcriptomics associated the RRS with RHAMM-high microanatomic foci. We conclude that RHAMM upregulation leads to the formation of ‘invasive niches’, which are enriched in RRS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes.

Original languageEnglish (US)
Pages (from-to)289-303
Number of pages15
JournalJournal of Pathology
Volume260
Issue number3
DOIs
StatePublished - Jul 2023

Keywords

  • breast cancer
  • cell division
  • extracellular matrix
  • hyaluronan
  • hyaluronan receptors
  • neoplasm invasiveness
  • tumor microenvironment
  • xenograft

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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