Browsing by Author "Chim, Letitia K."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Biomechanical forces in tissue engineered tumor models
    (Elsevier, 2018) Chim, Letitia K.; Mikos, Antonios G.
    Solid tumors are complex three-dimensional (3D) networks of cancer and stromal cells within a dynamic extracellular matrix. Monolayer cultures fail to recapitulate the native microenvironment and therefore are poor candidates for pre-clinical drug studies and studying pathways in cancer. The tissue engineering toolkit allows us to make models that better recapitulate the 3D architecture present in tumors. Moreover, the role of the mechanical microenvironment, including matrix stiffness and shear stress from fluid flow, is known to contribute to cancer progression and drug resistance. We review recent developments in tissue engineered tumor models with a focus on the role of the biomechanical forces and propose future considerations to implement to improve physiological relevance of such models.
  • Thumbnail Image
    Item
    Correlation of nuclear pIGF-1R/IGF-1R and YAP/TAZ in a tissue microarray with outcomes in osteosarcoma patients
    (Oncotarget, 2022) Molina, Eric R.; Chim, Letitia K.; Lamhamedi-Cherradi, Salah-Eddine; Mohiuddin, Sana; McCall, David; Cuglievan, Branko; Krishnan, Sandhya; Porter, Robert W.; Ingram, Davis R.; Wang, Wei-Lien; Lazar, Alexander J.; Scott, David W.; Truong, Danh D.; Daw, Najat C.; Ludwig, Joseph A.; Mikos, Antonios G.
    Osteosarcoma (OS) is a genetically diverse bone cancer that lacks a consistent targetable mutation. Recent studies suggest the IGF/PI3K/mTOR pathway and YAP/TAZ paralogs regulate cell fate and proliferation in response to biomechanical cues within the tumor microenvironment. How this occurs and their implication upon osteosarcoma survival, remains poorly understood. Here, we show that IGF-1R can translocate into the nucleus, where it may act as part of a transcription factor complex. To explore the relationship between YAP/TAZ and total and nuclear phosphorylated IGF-1R (pIGF-1R), we evaluated sequential tumor sections from a 37-patient tissue microarray by confocal microscopy. Next, we examined the relationship between stained markers, clinical disease characteristics, and patient outcomes. The nuclear to cytoplasmic ratios (N:C ratio) of YAP and TAZ strongly correlated with nuclear pIGF-1R (r = 0.522, p = 0.001 for each pair). Kaplan–Meier analyses indicated that nuclear pIGF-1R predicted poor overall survival, a finding confirmed in the Cox proportional hazards model. Though additional investigation in a larger prospective study will be required to validate the prognostic accuracy of these markers, our results may have broad implications for the new class of YAP, TAZ, AXL, or TEAD inhibitors that have reached early phase clinical trials this year.