Periodic Reporting for period 4 - Cancer-Recurrence (Tumor cell death supports recurrence of cancer)
Période du rapport: 2019-04-01 au 2020-08-31
State-of-the–art objectives and hypothesis:
Although all the universal aim of all the different therapies is to kill the tumor cells, the therapie itself can also influence the environment of the surviving tumor cells. This can potentially lead to cell states (e.g. EMT and stemness) that enable the surviving cells to spread and regrow (distant) tumors leading to recurrence. Therefore, we will study the unintended side-effects of therapies on the surviving tumor cells and stroma, identify the key cell types and mechanisms that mediate this effect, and test whether interference with these key cell types and mechanisms leads to reduced recurrence of tumors upon treatment. Since induction of cell death is the universal aim of therapy, interfering with unintended side-effects of tumor cell death may be a therapeutic avenue leading towards improved outcome of a wide range of therapies.
Hypothesis: Although therapies can kill the bulk of cancer cells, it potentially also has unintended and harmful side-effects on the remaining fraction of tumor cells and stroma, with subsequent profound consequences for the long-term outcome of cancer.
Main aim: Gain a better understanding on the unintended side-effects of therapies on the growth and dissemination of surviving tumor cells, with the ultimate goal to improve clinical strategies by reducing tumor recurrence.
Although biopsies have a prognostic benefit, potential negative effects of inducing cell death in the remaining tumor cells have also been suggested. Using a retrospect study of patients and intravital imaging study of mice, we have identified some of these negative aspects, including stimulation of proliferation and migration of non-resected cells, and provide a strategy to prevent these adverse effects. By repeated high-resolution intravital microscopy, we showed that biopsy-like injury induces migration and proliferation of tumor cells through chemokine (C-C motif) ligand 2 (CCL-2)-dependent recruitment of macrophages. Blocking macrophage recruitment or administrating dexamethasone, a commonly used glucocorticoid to treat inflammation, led to suppression of the observed inflammatory response and subsequent tumor growth upon biopsy both in mice and patients. Taken together, our study suggested that induction of cell death by needle biopsy induces an inflammation response with a subsequent enhancement of proliferation and migration in the non-resected cancer cells, and that inhibiting CCL-2-dependent recruitment of macrophages may further increase the clinical benefits from surgical and biopsy procedures.
Exploration:
For our research, we had to develop different new mouse models, intravital imaging tools, and single cell sequencing approaches to study whether surviving cancer cells undergo a phenotypic change (e.g. undergo epithelial-to-mesenchymal transition (EMT) or acquire stemness). We have used this tools to show the key roles of stem cell properties and EMT states to spread to distant sites and to induce (re)growth of tumors.
Dissemination:
The dissemination was multiple. We have disseminated our results to the scientific community by publishing >20 papers in high-impact journals such as Nature, Cell, and Cell Reports. Moreover, we disseminated our new tools and approaches by publishing protocol papers, and have shared reagents through e.g. Addgene (https://www.addgene.org/Jacco_van_Rheenen/). Moreover, our data was communicated by presentations at international meetings such as the AACR meetings, and to society by giving layman talks.