Browsing by Author "Rodriguez, B. Leticia"

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    A novel ex vivo tumor system identifies Src-mediated invasion and metastasis in mesenchymal tumor cells in non-small cell lung cancer
    (Springer Nature, 2019) Padhye, Aparna; Ungewiss, Christin; Fradette, Jared J.; Rodriguez, B. Leticia; Albritton, Jacob L.; Miller, Jordan S.; Gibbons, Don L.
    Lung cancer is the foremost cause of cancer related deaths in the U.S. It is a heterogeneous disease composed of genetically and phenotypically distinct tumor cells surrounded by heterotypic cells and extracellular matrix dynamically interacting with the tumor cells. Research in lung cancer is often restricted to patient-derived tumor specimens, in vitro cell cultures and limited animal models, which fail to capture the cellular or microenvironment heterogeneity of the tumor. Therefore, our knowledge is primarily focused on cancer-cell autonomous aberrations. For a fundamental understanding of lung cancer progression and an exploration of therapeutic options, we focused our efforts to develop an Ex Vivo Tumor platform to culture tumors in 3D matrices, which retains tumor cell heterogeneity arising due to in vivo selection pressure and environmental influences and recapitulate responses of tumor cells to external manipulations. To establish this model, implanted syngeneic murine tumors from a mutant KRAS/p53 model were harvested to yield multicellular tumor aggregates followed by culture in 3D extracellular matrices. Using this system, we identified Src signaling as an important driver of invasion and metastasis in lung cancer and demonstrate that EVTs are a robust experimental tool bridging the gap between conventional in vitro and in vivo models.
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    Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity
    (Cell Press, 2021) Bota-Rabassedas, Neus; Banerjee, Priyam; Niu, Yichi; Cao, Wenjian; Luo, Jiayi; Xi, Yuanxin; Tan, Xiaochao; Sheng, Kuanwei; Ahn, Young-Ho; Lee, Sieun; Parra, Edwin Roger; Rodriguez-Canales, Jaime; Albritton, Jacob; Weiger, Michael; Liu, Xin; Guo, Hou-Fu; Yu, Jiang; Rodriguez, B. Leticia; Firestone, Joshua J.A.; Mino, Barbara; Creighton, Chad J.; Solis, Luisa M.; Villalobos, Pamela; Raso, Maria Gabriela; Sazer, Daniel W.; Gibbons, Don L.; Russell, William K.; Longmore, Gregory D.; Wistuba, Ignacio I.; Wang, Jing; Chapman, Harold A.; Miller, Jordan S.; Zong, Chenghang; Kurie, Jonathan M.
    Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues from LUAD cells to promote metastasis.