"Being responsible for my own research project has been a great incentive to step out of my scientific comfort zone and explore areas less familiar to me such as Molecular Biology. These bacteria were transformed to produce a plasmid containing a synthetic piece of double stranded DNA I designed." - Lisi Krainer
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Interactions between the tumor, bone tissue and therapies used to treat the tumor are complicated by the differential effects of therapy on different populations of cells within the anatomic bone and the tumor. Further complicating therapeutic-outcomes are the interactions of therapies in a dynamic tissue environment and the interactions between cell populations negatively effected by therapy and those that remain unaltered.
Computational modeling will be required to develop more rational and less anecdotal therapeutic strategies. Thus, part of the long-term programmatic goal of my lab will be to develop predicative mathematical models that virtually test different combinations of cancer therapies against pediatric bone sarcomas and the expected post-therapeutic outcomes. I foresee that this work will lead to more targeted therapies tailored for a specific tumor and for a specific patient demographic. Further, it should be possible to expand this mathematical approach to examine the effects of therapy on bones treated for metastases from adult malignancies or to determine what perturbations during childhood predispose an adult to bone or cartilage diseases, such as osteoporosis or osteoarthritis.
Current computational approaches are limited to the molecular scale. An additional objective of my work is to couple molecular scale mathematics (statistical mechanics/ molecular dynamics) with topology, which is the branch of mathematics dealing with macro-scale events. This later work should allow for the creation of more global/systemic models.
The de-differentiated tumor cell phenotype is thought to correspond to a phenotype that is similar to an embryonic cell phenotype. This paradigm suggests that factors produced by the resident population of mesenchymal stem cells (MSC) could influence tumor cell survival and progression. Conversely, this paradigm also suggests that factors produced by tumor cells could influence MSC. In the later case, the tumor cell interaction with MSC could lead to alterations in fate determination concurrent with increased post-therapy complications that evolve from a decreased ability of the affected tissue to effectively repair. In the case of bone, therapy associated complications include fracture, osteoporosis and necrosis; all of which result in significantly increased morbidity. Thus, tumor cells may act to inhibit post-therapy repair by altering fate determination or reducing survival in MSC.
It is widely understood that the bone microenvironment is different in pediatric bone versus adult bone. However, how these differences in pediatric versus adult bone correspond to tumor growth remain unknown. Signaling pathways that are important to development and adult bone maintenance are Wnt, hedgehog, BMP, FGF and notch-signaling. While these signaling pathways have been observed in tumor cells, their respective role in tumor-bone interactions remains unknown. Thus, the complex interplay of these different signaling pathways active in bone may play a role in mediating tumor progression. Conversely, tumor mediated signaling with these pathways may alter bone and impact further tumor progression and post-therapeutic outcomes.
Bone matrix proteins engage in various cell functions that include cell adhesion, proliferation and migration. This is an emerging field of tumor biology, with most examinations of tumor-matrix interactions done in vitro. Surprisingly, this area of tumor biology has failed to make use of transgenic animals currently available with altered bone matrix. In addition, previous work has shown that radiation therapy, in particular, is capable of altering the bone matrix permanently. It is currently unknown how therapy or the tumor might independently change the bone matrix and subsequently result increased metastasis or increased morbidity.