Date of Award
Medical Doctor (MD)
Therapies such as chemotherapy and molecularly targeted therapy are the mainstays for cancer treatment but have their distinct drawbacks. The latest immunotherapies, while highly effective in certain tumors, fail to elicit a response in more than half of patients. New, alternate modalities to treating cancer are urgently needed. Most therapies target cancer cells, without regard to their surrounding tumor stroma, even though the tumor stroma is an active player in cancer initiation and invasion. Can tumor stroma be reprogrammed to inhibit cancer instead, as a novel modality to treat cancer? We use basal cell carcinoma (BCC) as a proof-of-concept model, as this follicular cancer distinctively lacks specialized fibroblasts (dermal condensates) in its tumor stroma that are normally present in hair follicles and associated benign tumors, and which are normally required for the differentiation of the epithelium into follicular fate. We hypothesize that inserting such hair-inductive fibroblasts into BCC stroma could cause differentiation and thereby suppression of cancer. First, by using lineage tracing and two-photon microscopy, we show for the first time that these fibroblasts in normal hair follicles are formed by the directional migration of Wnt-active upper dermal cells using actomyosin networks, with sonic hedgehog signaling being critical to their identity. Second, by co-transplanting these fibroblasts with BCC cells into immune-deficient mice, we find that BCC tumors are suppressed by engaging programs of differentiation. Tissue analysis show significantly decreased markers associated with malignancy and stem cell identity (Sox9, P-Cad, EdU) and increased markers of differentiation (keratin, keratohyalin granules, K10). Collectively, this study shows that activating the tumor stroma to promote normal epithelial differentiation in malignant cells may be a novel and effective modality to treat cancer.
Sun, Thomas Yang, "A New Modality For Treating Cancer: Activating The Tumor Stroma" (2017). Yale Medicine Thesis Digital Library. 2175.