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 E Daughters, Todd P. Knutson, Christy Henzler, Matthew A Price, Ryan Shanley, Patrice M 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


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
Issue number3
StatePublished - Jul 2023

Bibliographical note

Funding Information:
This work was supported in part by the University of Minnesota Masonic Cancer Center and Minnesota Masonic Charities. We acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing high performance computational resources. We also acknowledge Branden Moriarty (Genome Engineering Core, Masonic Cancer Center) for his help in designing the CRISPR system to knock out . This research received histology and immunohistochemistry assistance from the University of Minnesota's Biorepository and Laboratory Services program and was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. We wish to thank all the scientists and research support staff at the University of Minnesota Genomics Center, University Imaging Center, and Laboratory Medicine and Pathology, who helped to make this work possible. ACN is supported by the American Cancer Society (132574‐CSDG‐18‐139‐01‐CSM) and is an Eastern Star Scholar, Minnesota Masonic Charities. SET is supported by IRACDA‐TREM Postdoctoral Fellowship (K12GM119955). KLS is supported by the NIH R01CA215052, R01HD095858, and R01CA265004. ET and CT are supported by the Breast Cancer Society of Canada and the Cancer Research Society/Canadian Institutes of Health Research (945897). JBM is funded by the Atwater Fund, the Elsa U. Pardee Foundation, and the University of Minnesota Department of Laboratory Medicine & Pathology Chairman's Fund Professor in Cancer Research. RHAMM

Publisher Copyright:
© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


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


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