Kaisa Lehti Group
Tumor Cell – Microenvironment Commnication in Cancer Invasion, Metastasis and Drug Resistance
Phenotypic cell plasticity, including interchangeable modes of invasion and growth, contribute to cancer metastasis and drug resistance, representing a major challenge in cancer research. Multiple tumor microenvironment (TME) communication pathways are emerging, but it remains unclear how tumor cells integrate changes in cell-cell interactions and cues or physical confines of the extracellular matrix with cytoskeletal dynamics and intracellular signaling to produce TME-dependent plasticity in invasion and growth control.
Our results have revealed unique mechanisms of migration signaling in collective invasion or epithelial-to-mesenchymal transition-induced cancer invasion and metastasis (see Turunen et al. 2017). These include dynamic interactions and signaling crosstalk of receptor tyrosine kinases (RTK) with membrane-anchored proteases and adhesion molecules in tumor and stromal cells, as well as unique tumor cell cytoskeletal interactions. By systematic RTK (FGFR & Eph) interaction screens and kinase substrate identification, our ongoing research will identify unexpectedly specific physical and functional interactions that coordinate the crosstalk with cell cytoskeleton and polarity & growth or apoptosis pathways in aggressive breast cancers. In melanoma, we described a phenotypic switch from collagen infiltration to lymphovascular invasion, linear collagen assembly and tumor cell aggregation upon induction of the membrane-type matrix metalloproteinase MMP16 in the most aggressive tumors. In recent collaborative studies we identified a context dependent reciprocal communication system between melanoma cells and lymphatic endothelial cells, as well as a novel transcriptional regulatory mechanism of pro-invasive MMP14 in endothelial and cancer cells. We also found that the processes of lymphatic-like neovascularization and endothelial differentiation co-exist with endothelial progenitor cell activation in proliferative diabetic retinopathy.
Our current main research focus is on ovarian cancer (OC), which spreads aggressively via peritoneal fluid to abdominal organs, developing resistance to often initially effective chemotherapy. Putative resistance and recurrence driving TME communication pathways activated during OC evolution and under selective pressure of therapy in the metastasized tumors remain elusive. Our results from patient derived 3D cell and tissue models in combination with proteomic, genetic and clinical data analysis, as well as quantitative live cell imaging of stroma-OC communication, will reveal specific extracellular matrix-integrin pathways and Eph-receptor mediated oncogenic signals in adaptive OC chemoresistance.
|Twana Hasseb Abdulahad Alkasalias||Anknuten|
|Yuichiro Miki||Anknuten, Postdoc|
|Lidia Moyano Galceran||Doktorand, Forskarstuderande|