TGFβ and Hippo pathways cooperate to enhance sarcomagenesis and metastasis through the hyaluronan mediated motility receptor (HMMR)

Ye, S., Liu, Y., Fuller, A.M., Katti, R., Ciotti, G.E., Chor, S., Alam, M.Z., Devalaraja, S., Lorent, K., Weber, K., Haldar, M., Pack, M.A., Eisinger-Mathason, T.S.K.
Molecular cancer research : MCR   18(4): 560-573 (Journal)
Registered Authors
Lorent, Kristin, Pack, Michael
MeSH Terms
  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Animals, Genetically Modified
  • Cell Line, Tumor
  • Extracellular Matrix Proteins/metabolism*
  • Fibrosarcoma
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Hyaluronan Receptors/metabolism*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Protein Serine-Threonine Kinases/metabolism*
  • Sarcoma/metabolism*
  • Sarcoma/pathology
  • Transcription Factors/metabolism
  • Transforming Growth Factor beta/metabolism*
  • Zebrafish
31988250 Full text @ Mol. Cancer Res.
High-grade sarcomas are metastatic and pose a serious threat to patient survival. Undifferentiated pleomorphic sarcoma (UPS) is a particularly dangerous and relatively common sarcoma subtype diagnosed in adults. UPS contain large quantities of extracellular matrix (ECM) including Hyaluronic Acid (HA), which is linked to metastatic potential. Consistent with these observations, expression of the HA receptor, hyaluronan-mediated motility receptor (HMMR/RHAMM), is tightly controlled in normal tissues and upregulated in UPS. Moreover, HMMR expression correlates with poor clinical outcome in these patients. Deregulation of the tumor suppressive Hippo pathway is also linked to poor outcome in these patients. YAP1, the transcriptional regulator and central effector of Hippo pathway, is aberrantly stabilized in UPS and was recently shown to control RHAMM expression in breast cancer cells. Interestingly, both YAP1 and RHAMM are linked to TGFβ signaling. Therefore, we investigated crosstalk between YAP1 and TGFβ resulting in enhanced RHAMM-mediated cell migration and invasion. We observed that HMMR expression is under the control of both YAP1 and TGFβ and can be effectively targeted with small molecule approaches that inhibit these pathways. Furthermore, we found that RHAMM expression promotes tumor cell proliferation and migration/invasion. To test these observations in a robust and quantifiable in vivo system we developed a zebrafish xenograft assay of metastasis, which is complimentary to our murine studies. Importantly, pharmacological inhibition of the TGFβ-YAP1-RHAMM axis prevents vascular migration of tumor cells to distant sites. Implications: These studies reveal key metastatic signaling mechanisms and highlight potential approaches to prevent metastatic dissemination in UPS.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes