The impact of CD44 on the metastatic microenvironment: pre-metastatic and metastatic niches

• Applicant: Professorin Dr. Véronique Orian-Rousseau
• Subject Area: Cell Biology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329561212

Although tremendous progress has been made in cancer treatment, metastasizing cancers still remain a challenge for oncologists. It is now clear that the metastatic process is not exclusively orchestrated by cancer cells but is also influenced by the stroma. VEGFR-1+ bone marrow derived cells (BMDCs) and CD11b+ cells have been shown to be involved in the metastatic niche preparation. A plethora of factors amongst which extracellular matrix components (ECM) such as fibronectin, chemokines and growth factors attract cancer cells to distant organs. One important player in the metastatic process is CD44. Our group has demonstrated a role of CD44v6, one member of the CD44 family, as a co-receptor for the receptor tyrosine kinases MET and VEGFR-2. A CD44v6 peptide could inhibit angiogenesis, decrease tumor growth and inhibit metastasis of pancreatic cancer cells (Matzke-Ogi et al., Gastroenterology, 2016). Most interestingly, the CD44v6 peptide also induces apoptosis of metastatic cells in distant organs suggesting a contribution of CD44 to the maintenance of these cells in target organs. Preliminary data indicate that CXCL12-induced migration of bone marrow cells and of the FACS sorted CD11b+;CD45+ cells is inhibited by an antibody against CD44. Additional results show an impairment of chronic lymphocytic leukemia cells to the spleen in the Cd44 germ-line knockout mouse showing the importance of CD44 in the microenvironment. In this grant application we will study the role of CD44 specifically on the side of the microenvironment. More precisely we will analyze the function of CD44 in the formation of the pre-metastatic niche and in the maintenance of this niche. One approach to achieve this goal will be to use the Cd44 (or Cd44v6) floxed mouse crossed with the Vav-CreERT2 mice and the B6.129X1-Gt(ROSA)26Sortm1(EYFP)Cos/J (short: R26-LSL-EYFP) mouse to remove Cd44 (or Cd44v6) in the hematopoietic system. In addition in the Cd44fl/fl; Vav-CreERT2; R26-LSL-EYFPKI/KI mice the BMDCs that are Cd44 negative will be labeled with EYFP and will be tracable. Metastasis of the Lewis lung carcinoma, PancO2 and B16 melanoma cells labeled with a red fluorescent protein will be studied in mice bearing Cd44 negative BMDCs. We expect to answer two questions: 1) Do BMDCs migrate to the future niche in the absence of CD44. 2) Does the lack of CD44 on BMDCs impact the formation of the metastatic niche and the settlement in the metastatic niche. Moreover, removal of CD44 will also be performed after metastasis has occurred to test the contribution of CD44 to the maintenance of the metastatic niche. These studies will allow unraveling a completely new aspect of the contribution of CD44 to the metastatic process. Defining the precise mode of action of CD44 involved in niche formation and maintenance will contribute to increase the understanding of the metastatic process thereby possibly allowing the development of new tools to interfere with metastasis formation.

• DFG Programme: Research Grants