October is Breast Cancer Awareness Month in the US. We spoke with University of California, San Diego graduate student Pranjali Beri and her PI, BPS member Adam J. Engler, about their research on breast cancer and other epithelial-based cancers.
What is the connection between your research and cancer?
Cancer is the second leading cause of death in the US, resulting in approximately 600,000 deaths in 2016. The negative prognosis associated with cancer is due in large part to metastasis of a primary tumor. Cancer metastasis is the process by which tumor cells leave the primary tumor, enter the blood stream (intravasation), exit the blood stream at a different site in the body (extravasation), and establish a secondary tumor. However, tumors are exceedingly heterogeneous and only a small fraction of cancer cells from the primary tumor are capable of establishing secondary tumors. The metastatic potential of identical solid tumor types also varies from patient-to-patient due to expression differences of critical markers, making it nearly impossible to identify a universal biomarker that can predict metastatic potential of all solid tumors.
Cancer cell migration away from the primary tumor is driven, in part, by physical interactions between cells and the surrounding extracellular matrix. Protein clusters known as focal adhesions allow cells to attach to the matrix proteins, and stability and strength of these attachments plays a role in regulating cancer cell migration. Our research is attempting to understand the link between adhesion strength via focal adhesions and cancer cell dissemination. In our recently publication, we quantify population adhesion strength of various epithelial cancer cell lines by utilizing a spinning-disk shear assay (Figure 1a). The shear stress required to detach 75% of the cell population serves as a metric to describe the adhesion strength of that population. In the presence of conditions that mimic the tissue adjacent to tumors, e.g. low divalent cations, we found that heterogeneous adhesion strength for the most aggressive cells indicate that subpopulations within aggressive cell lines were capable of metastatic behavior. This is similar to the small fraction of the primary tumor previously thought to contain stem cell-like properties of self-renewal, differentiation, and migration.
Currently, our research further seeks to sort, capture, and analyze cells with more labile focal adhesions in response to stromal cation concentrations. We have developed a parallel plate flow chamber assay to isolate weakly adherent cells (Figure 1b) and characterize their migratory propensity in relation to strongly adherent as well as unselected cell populations. By demonstrating that there is a link between adhesion strength and migratory propensity of the cancer cells, we can use it as a biophysical marker for metastatic potential.
Why is your research important to those concerned about cancer?
Epithelial tumors, or carcinomas, are the most common type of cancer. There is no universal biomarker that acts as an indicator for metastatic potential. However, most epithelial cancers undergo metastasis. Having a physical indicator of metastasis can be beneficial in identifying the aggressiveness of a tumor and its likelihood of forming secondary metastases, independent of the type of epithelial tumor that it is.
How did you get into this research?
Throughout my undergraduate career, I have been interested in microfluidic devices and their applications as diagnostic devices. In graduate school, I joined the Engler lab in order to apply my microfluidics background towards cancer metastasis research.
How long have you been working on it?
I began working with microfluidic devices during my undergraduate studies. However, it was in graduate school that I used it to study cancer cell dissemination.
Do you receive public funding for this work? If so, from what agency?
I am currently funded by the National Science Foundation through their Graduate Research Fellowship Program. This research is also funded by the National Institute of Health and the Department of Defense Congressionally Directed Medical Research Program.
Have you had any surprising findings thus far?
Tissue adjacent to tumors has dramatically lower ion concentrations than in the tumor. In our previous publication, heterogeneity is most pronounced in highly metastatic cancer cell lines, but only when exposed to low ion conditions that mimic adjacent tissue; in the presence of high cation concentration, akin to the tumor microenvironment, metastatic cells are mechanically indistinguishable from their non-metastatic counterparts. This shift in adhesion strength was not present in non-metastatic cancer cell lines but was present in epithelial cancer cell lines from other tumors as well, including prostate and lung. While these previous studies could isolate the strongly adherent fraction remaining attached, recent experiments using flow chamber assays indicate that weakly adherent cells from the same cell lines display increased migration speed and are more processive in comparison to unsorted or strongly adherent populations. These results indicate that adhesion strength can potentially act as a biophysical marker of metastatic potential, and that the weakly adherent cells are likely to have the highest metastatic potential.
What is particularly interesting about this work from the perspective of other researchers?
Our fluidic-based separation method could allow us to isolate cancer cells by their metastatic potential. The adhesion strength-based separation method can serve as a potential prognostic device that exposes patient biopsies to shear stress, correlates weakly adherent cell isolation with metastatic potential, and makes a prognostic determination about the likelihood to metastatic disease in the future.
What is particularly interesting about this work from the perspective of the public?
By establishing the link between adhesion strength of the cells in the tumor and the metastatic potential of the tumor, we can ascertain the aggressiveness of patient tumors and tailor treatments accordingly.