22 November

Thesis defense Daniëlle Seinstra: investigating tumor cell behavior

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Daniëlle Seinstra from the Van Rheenen group, a former research group of the Hubrecht Institute currently located at the Netherlands Cancer Institute (NKI), successfully defended her thesis on the 22nd of November. Seinstra investigated several components of tumor heterogeneity and plasticity in breast cancer using various techniques such as intravital microscopy and single cell sequencing in human breast tumors.

Medical doctor and Molecular biologist
While studying to become a medical doctor, Seinstra also did a research master to be able to combine her interests in medicine and understanding the basic mechanisms of health and disease. During this research master she did her internship in the group of Jacco van Rheenen after which she came back for to do her PhD. Now that her PhD is finished, Seinstra will start specializing to become a pathologist. Seinstra believes that the combination between medicine and basic research will help her to set up important collaborations that will help new scientific results to get to the clinic faster. 

Tumor heterogeneity and plasticity
Breast cancer is the most common cancer in women; 30% of cancer diagnoses in women worldwide are breast cancer. Breast cancer tumors are very heterogeneous: different cells within the same tumor can have different characteristics. In addition, cells in a tumor can change their behavior and characteristics depending on other cells in their environment. This is called plasticity. Better understanding of such tumor characteristics and their role in tumor progression and treatment response can ultimately increase patient survival. Seinstra therefore studied tumor heterogeneity and plasticity during her PhD.

Identifying new targets for treatment

E-cadherin loss is a hallmark of epithelial-to-mesenchymal transition, a process that is considered for metastasis of a tumor. Seinstra used a mouse model in which loss of endogenous E-cadherin in breast tumor cells can be tracked through a color change in these cells upon loss of E-cadherin. She found that all tumor cells that migrate have lost E-cadherin. However, both cells with and without E-cadherin were observed in the blood and both had a similar capacity to grow into metastases. Upon leaving the blood stream, cells that had lost E-cadherin needed to re-initiate E-cadherin expression, i.e. undergo mesenchymal-to-epithelial transition, to be able to effectively form metastases. These results show that tumor cell plasticity is required for efficient metastasis.

Seinstra found that overexpression of C/EBPa, a gene that is normally inhibited during the epithelial-to-mesenchymal transition, could keep tumor cells in an epithelial state, which inhibited metastasis in vivo in mice. This may provide an interesting treatment option in the future, although there are currently no drugs available that upregulate the expression of C/EBPa.

Characterization of tumor heterogeneity in patients
To study tumor heterogeneity, Seinstra performed single cell RNA sequencing on breast cancer tumors from ten patients, resulting in gene expression profiles of individual cells from these tumors. She found that the contribution of various cells to the tumors, and therefore the heterogeneity, was different between patients. Because this experimental setup is too time intense and costly to use in the clinic, the single cell sequencing data were used to develop a computational algorithm -called Tumor Cell Deconvolution- in collaboration with the Van Oudenaarden group at the Hubrecht Institute. Using this algorithm on bulk sequencing data, in which a piece of the tumor is sequenced at once instead of the individual cells, can be used to determine the abundance of certain types of cells in the tumor. Using such bulk sequencing data from patients for which the response to therapy was followed for seven years, Seinstra identified heterogeneity markers that can predict the response to certain therapies and patient survival. These heterogeneity markers may be used in the clinic in the future to personalize treatment for breast cancer patients.

 

Jacco van Rheenen is a former group leader of the Hubrecht Institute and current group leader at the Netherlands Cancer Institute (NKI) in Amsterdam. Van Rheenen is Professor of Intravital Microscopy at Utrecht University and Oncode Investigator.