Squamous cell carcinoma of the bronchus is the second most common and fatal subtype of lung cancer. In the process of squamous carcinogenesis, the normal bronchial epithelium undergoes a series of histologic transformations known as the metaplasia-dysplasia-carcinoma sequence. These intermediate histologic patterns are called premalignant lesions, and occur prior to the development of cancer. Compared to early stage cancer, survival following resection of premalignant lesions approaches 100%, highlighting the promise of lung cancer interception. However, because of our lack of understanding of the molecular events during squamous carcinogenesis, we are currently unable to predict which lesions will progress to cancer, and we do not have molecular targets for noninvasive treatment. The work in this thesis seeks to improve our understanding of the changes associated with grades of premalignant histology and progression at the level of single cells.
I analyzed single cell RNA sequencing data from a cohort of 41 lesions from 26 patients, encompassing the normal-appearing bronchus, premalignant lesions, and early stage carcinoma. I described histology-associated changes in basal cells. Basal cells from low grade lesions expressed genes related to the maintenance of the normal epithelium, while basal cells from high grade lesions expressed genes related to the cell cycle and detoxification of the airway from smoking toxicants. Secondly, I identified a high grade lesion undergoing the epithelial-to-mesenchymal transition. These cells transitioned from a high grade basal cell state, lost their expression of basal cell markers, and expressed canonical EMT genes, including SPARC, FN1, and MMP2. Finally, I identified shifts in T cell subtypes and widespread expression of exhaustion markers PD-1, CTLA4, LAG3, and TIGIT co-occurring with high grade basal cells.
Secondly, I leveraged our single cell data to identify gene modules associated with histology and progression in bulk RNA sequencing data. I identified a module of genes expressed in B and dendritic cells involved in antigen presentation through the MHC II pathway whose expression was decreased in progressive lesions. I also identified a module of stromal-expressed genes that were less expressed in progressive lesions, which had previously been unidentified. Associations between module expression and progression were validated in a second data set.
This work improves our understanding of the signaling and interactions between cell types associated with histology and progression of premalignant lesions. These findings may be used to improve our prognostication and treatment of premalignant lesions.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48085 |
| Date | 12 February 2024 |
| Creators | Shea, Conor |
| Contributors | Lenburg, Marc |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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