Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Primary carcinomas and metastases are complex organ-like structures composed of malignant parenchymal epithelial tissues and a desmoplastic stroma formed by accumulation of hematopoietic cells, mesenchymal stromal cells and extracellular matrix. The crosstalk between malignant epithelial cells and tumor stroma is becoming increasingly appreciated as a key determinant in tumor development, progression and metastasis, as well as inducing resistance to various cancer treatments including chemotherapy, radiotherapy and immunotherapy. Mechanistic understanding of how the tumor-stromal interaction contributes to tumor progression and therapeutic resistance will advance cancer therapies and improve clinical management, especially for patients with metastatic disease. Fibroblast activation protein (FAP) is a membrane surface protease found overexpressed in cancer-associated stromal cells. Overexpression of FAP is associated with tumor progression, metastasis and recurrence, and predicts a poorer prognosis in many types of human tumors. The central goal of my thesis project is to investigate whether FAP protease and/or FAP protease-expressing stromal cells play essential roles in tumor progression and metastasis. In collaboration with Drs. Steven Albelda and Carl June’s groups, we generated chimeric antigen receptor (CAR) T cells redirected against FAP+ stromal cells to study their impact on tumor progression. Conditional depletion of FAP+ stromal cells by FAP-CAR T cells restrains tumor progression without causing severe toxicity. Mechanistic investigations revealed that FAP+ stromal cells promote tumor growth via immune suppression and immune-independent remodeling of the stromal microenvironment. Additionally, using FAP-deficient mice, I found that FAP protease promotes early malignant cell seeding and pulmonary metastatic outgrowth, possibly through regulating coagulation pathways and the inflammatory response, respectively. Finally, I observed that FAP protease promotes pancreatic cancer development, as its deletion delays the progression of preneoplastic lesions and tumor formation in a genetically engineered mouse model of pancreatic ductal carcinoma. FAP protease is also essential for inducing pancreatic cancer resistance to necrotic cell death and promoting metastasis and outgrowth in multiple target organs. Together, these findings demonstrate that molecular and cellular targeting of FAP represents a promising therapeutic approach for a variety of solid tumors.
Lo, Albert, "Finding Common Ground to Treat Primary and Metastatic Cancer: The Potential of Targeting Tumor Stroma" (2016). Publicly Accessible Penn Dissertations. 1862.
Available for download on Saturday, March 02, 2019