Characterization of Fibroblasts and Their Role in the Tumor Microenvironment:

Lung cancer is the leading cause of cancer-related deaths world-wide. Patient prognosis is often poor and fewer than 15% survive past 5 years (Guyard et al 2017). There are two main categories of lung cancer: small cell and non-small cell (Herbst et al 2008). Non-small cell lung cancer is histologically characterized into three additional subtypes: squamous-cell carcinoma, adenocarcinoma, and large-cell lung cancer (Herbst et al 2008).  Available treatment options include standard chemotherapy and radiation, both of which compromise patient quality of life. Despite the expansion of these therapeutics, molecular mechanisms governing lung cancer development remain largely unknown (Guyard et al 2017). 

 Current biomedical research has demonstrated the significance of the tumor microenvironment (TME), which aids the proliferation and survival of malignant tumors through cell-cell interactions or secretory effects (Kalluri 2016). Immune cells, capillaries, activated fibroblasts, and extracellular matrix proteins all comprise the TME, and each play important roles in tumorigenesis (Kalluri 2016). Fibroblasts, in particular, have been documented to utilize paracrine signaling and extracellular matrix (ECM) deposition to promote the growth and of surrounding cells,(so/and?) therefore have become an attractive area for cancer research (Kalluri 2016). In the context of cancer, fibroblasts transform from a quiescent state to an activated one, otherwise known as cancer activated fibroblasts (CAFs) (Kalluri 2016). This phenotypic change is dependent on several molecular factors, including autocrine and immunomodulatory signaling (Kalluri 2016). Although fibroblast activation has been described in cancer-related literature, the dynamic relationship between fibroblasts, the immune system, and cancer cells remains elusive.

The research focuses of our laboratory are the transcription factor c-Jun and fibroblasts in the context of fibrosis and cancer. Previous work in our laboratory established a unifying mechanism for fibrotic disease, whereby c-Jun overexpression drives fibrosis in several organs including the skin, liver, and lung (Wernig et al 2017). Using a c-Jun inducible combined with bleomycin mouse model (Shieh et al 2019), we propose to investigate the discrete molecular signaling pathways between immune cells and fibroblasts that promotes fibrosis and subsequent tumorigenesis. By researching these interactions, we can compile specific and effective targets for therapeutics with the overall objective of improving patient prognosis and quality of life.