(638g) Combining Systems Biology and Bioprocessing: Opportunity for Cancer Stem Cell Bioprocessing

In the emerging era of personalized medicine, the dream is to provide individualized translational research so that each patient could receive a more personalized, targeted therapy. This requires doing translational research using the patients’ own tumor samples, but a major hurdle is the scarcity of the cells obtainable from freshly dissociated patient samples. Although difficult-to-attain, such cells provide a more clinically relevant and meaningful information than established cell lines. Yet expansion by serial, long-term culture of these cells typically changes their original phenotype and even genotype. Therefore, it remains critical to develop a quick, efficient expansion system of newly dissociated patient samples in order to perform adequate personalized preclinical translational research.

Unlike traditional cell lines that are often grown in adherent manner in complex media containing animal sera, the original characteristics of the patient-derived cells are better maintained in sphere-forming, stem cell culture media. As cells divide, they generate tumor cell spheres that retain the original characteristics, but when spheres grow too large in typical static cultures, it leads to mass transfer limitations that cause cell death. A well-controlled culture environment will be important, especially since it is the cells themselves that are the desired products (as opposed to, e.g., protein production). These challenges provide a unique opportunity for biochemical engineers to develop a sphere-forming submerged culture bioprocessing system, and a prototype is proposed here.

In addition, utilizing the hypothesis of cancer stem cells can aid in the proposed in vitro expansion. The hypothesis states that in the heterogenous tumor mass, there exists stem-cell like tumor cells that are uniquely endowed to form tumor, have self-renewal capacity and are inherently resistant to chemotherapy and/or radiation. For some solid tumors, particular surface markers have been identified that allow prospective isolation of cancer stem cells. For example in glioblastoma, the most malignant form of brain tumor, CD133(+) cells were originally proposed to correspond with cancer stem cells. However, recent reports are starting to challenge this original characterization, and other markers are starting to be considered, such as CD15(+) and/or HGFR(c-Met)(+). Also in breast cancer, the original CD24(-/low) CD44(+) cancer stem cell markers are now considered insufficient and the more recent studies include adding Lin(-), EpCAM(+) and/or ALDH(+). In addition, with many of these surface markers, it remains unclear as to what actual biological function they provide to the cancer stem cells. Therefore, a systems biology approach would be appropriate in better characterizing the stem cell population of the tumor mass. In particular, membrane subproteomics approach of patient-derived tumor cells is proposed.

The system proposed here of combining systems biology approach with bioprocess development for cancer stem cell engineering will function as a bridge-builder between the traditional preclinical translational researchers and bioprocess engineers. Because the conditions for growing cancer stem cells are similar to stem cell culture, our proposed work has broad applicability in the future to the field of cancer research as well as stem cell bioprocessing.