Integrative analysis of molecular and cellular mechanisms underlying therapy failure and local recurrence of head and neck cancers after surgery

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Head and neck squamous cell cancer (HNSCC) is a common and fatal disease. The poor survival of patients afflicted with these cancers is mostly a consequence of recurrent disease. Within our previous work, we developed an orthotopic mouse tumor model as a pre-clinical experimental platform to study local recurrence formation after surgery. Using an un-supervised multilevel (protein, mRNA, and miRNA) strategy, we found that in contrast to primary tumors, recurrent head and neck tumor cells undergo a stable genetic conversion towards a less proliferative but invasive and anti-apoptotic phenotype (i.e. up-regulation of u-PA, SMRA3; down-regulation of Mybbp1a, caspase 3, Ki67, miR 106a, miR 196b). Further functional studies provided experimental evidence that certain proteins (i.e. FOXM1, Mybbp1a) govern the switch between an invasive and proliferative phenotype. Based on these data, we hypothesize on the presence of a critical subpopulation of tumor cells (recurrent tumor initiating cells (R-TIC)) with the above-described features that give rise to post-surgical recurrence. Therefore, we intend to focus on two topics within our joint research project: First, we plan to confirm the role of identified key molecular circuitries that govern the switch of tumor cells from proliferation to invasion. Second, we will trace the progress of the invasive residual tumor cell populations that may contain R-TICs after surgery on a molecular level into macroscopic recurrent tumors and characterize the role of the above named and possibly novel circuitries in this process.