Werba, G. | bioRxiv Science

bioRxiv2022

Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified TIGIT as the major inhibitory checkpoint molecule of CD8+ T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

cancer biology↗

bioRxiv2021

Recurrence of cancer cell states across diverse tumors and their interactions with the microenvironment

While genetic tumor heterogeneity has long been recognized, recent work has revealed significant variation among cancer cells at the epigenetic and transcriptional levels. Profiling tumors at the single-cell level in individual cancer types has shown that transcriptional heterogeneity is organized into cancer cell states, implying that diverse cell states may represent stable and functional units with complementary roles in tumor maintenance and progression. However, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Furthermore, the role of cancer cell states in tumor progression and their specific interactions with cells of the tumor microenvironment remain to be elucidated. Here, we perform a pan-cancer single-cell RNA-Seq analysis across 15 cancer types and identify a catalog of 16 gene modules whose expression defines recurrent cancer cell states, including stress, interferon response, epithelial-mesenchymal transition, metal response, basal and ciliated. Using mouse models, we find that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Moreover, spatial transcriptomic analysis further links the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance, and metastasis.

cancer biology↗