Cancer progression is determined by intrinsic changes in the developing cancer cells as well as by important interactions between the cancer cells and other components of the tumor microenvironment. Lung cancer is the leading cause of cancer death in the United States and woridwide. Despite recent progress in lung cancer treatment, long-term survival rates for individuals with late-stage disease remain very poor. Using a wellstudied mouse model of invasive and metastatic non-small cell lung cancer (NSCLC) as well as human lung cancer cell lines and human cancer specimens, we will characterize and functionally test components of the extracellular matrix (ECM) and a specific cell type within tumor stroma for their effects on tumor biology, including tumor progression. Project 2 has three Specific Aims.
Aim 1 is focused on functional characterization of Tenascin C (TNC), an ECM component that has been implicated in tumor progression in a variety of settings, including in this model of NSCCL. We will use both cell-based and whole animal approaches to examine the effects of manipulation of TNC function on cancer progression.
In Aim 2, we will use an ECM microarray to identify additional ECM components that participate in cancer cell adhesion and may affect aspects of invasive and metastatic behavior. Screening studies, which will be carried out with cells of both mouse and human origin, will be followed by functional analysis.
Aim 3 utilizes advanced methods in genetic engineering to manipulate cancer-associated fibroblasts within established, late-stage NSCLC, in order to investigate the consequences of gross and more subtle alternations within this cell population for cancer cell biology. The methods developed for this purpose can also be applied to the study of other cancer-associated cell populations within the tumor microenvironment. This project has the potential to uncover tumor-stromal interactions that mediate critical aspects of cancer progression. The functional validation of these interactions could lead to new therapeutic strategies for treating NSCLC in humans and/or to prevent its progression. Project 2 is well integrated into the larger structure of this TMEN application through multiple interactions with each of the other projects and investigator groups.
|Kulkarni, Madhura; Tan, Tuan Zea; Syed Sulaiman, Nurfarhanah Bte et al. (2018) RUNX1 and RUNX3 protect against YAP-mediated EMT, stem-ness and shorter survival outcomes in breast cancer. Oncotarget 9:14175-14192|
|Kwan, Byron H; Zhu, Eric F; Tzeng, Alice et al. (2017) Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses. J Exp Med 214:1679-1690|
|Li, Ran; Hebert, Jess D; Lee, Tara A et al. (2017) Macrophage-Secreted TNF? and TGF?1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways. Cancer Res 77:279-290|
|Gocheva, Vasilena; Naba, Alexandra; Bhutkar, Arjun et al. (2017) Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival. Proc Natl Acad Sci U S A 114:E5625-E5634|
|Roper, Jatin; Tammela, Tuomas; Cetinbas, Naniye Malli et al. (2017) In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat Biotechnol 35:569-576|
|Engblom, Camilla; Pfirschke, Christina; Zilionis, Rapolas et al. (2017) Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358:|
|Naba, Alexandra; Clauser, Karl R; Mani, D R et al. (2017) Quantitative proteomic profiling of the extracellular matrix of pancreatic islets during the angiogenic switch and insulinoma progression. Sci Rep 7:40495|
|Carmona, G; Perera, U; Gillett, C et al. (2016) Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE. Oncogene 35:5155-69|
|Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen et al. (2016) Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 44:343-54|
|De Cock, Jasmine M; Shibue, Tsukasa; Dongre, Anushka et al. (2016) Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency. Cancer Res 76:6778-6784|
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