S

Epithelial-mesenchymal transition

Kamil Grzyb PhD student at ICS

LCSB

What is EMT (or MET)

Where EMT is present

S  EMTs are associated with S  embryo implantation,

S  embryogenesis,

S  organ development,

S  wound healing

S  But also contributes pathologically to fibrosis or cancer metastasis

Cancer metastasis with EMT

Nature 493, 487–488 (24 January 2013)

Triple-transgenic mouse model

ü  Mouse models of breast cancer metastasis (MMTV - PyMT) ü  Fsp1 is the critical gatekeeping gene of EMT initiation ü  Cre-switchable fluorescent marker under the control of the �-actin

promoter (Rosa26) – irreversible!

Confirming the E(RFP+) and M(GFP+) phenotype

Primary tumor & lung metastasis stained

Tumor graft for EMT

2% GFP+ 98% RFP+

GFP+ EMT tumour cells did not contribute to lung metastasis

Validating EMT lineage tracing system

EMT lineage tracing system

Almost no Mesenchymal

originated metastasis

In vivo spreading of tri-PyMT cells.

Inhibit EMT with miR-200

M cells chemoresistance(CTX)

•  Mice treated with cyclophosphamide (CTX) •  60% tumor reduction (by êgrowth and éapoptosis) •  GFP+(mesenchymal) cell count remained static.

miR-200 cancel M resistance

RNA-sequencing

Summing up…

S  Tumour cells disseminate and form metastases while persisting in their epithelial phenotype.

S  miR-200 (EMT inhibitor) has no effect on metastasis

S  Non-EMT cells are sensitive to chemotherapy

Other ways that EMT possibly contribute to cancer metastasis?

Tamoxifen-Cre