Coordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype

Abstract

Bulk analyses of pancreatic ductal adenocarcinoma (PDAC) samples are complicated by the tumor microenvironment (TME), i.e. signals from fibroblasts, endocrine, exocrine, and immune cells. Despite this, we and others have established tumor and stroma subtypes with prognostic significance. However, understanding of underlying signals driving distinct immune and stromal landscapes is still incomplete. Here we integrate 92 single cell RNA-seq samples from seven independent studies to build a reproducible PDAC atlas with a focus on tumor-TME interdependence. Patients with activated stroma are synonymous with higher myofibroblastic and immunogenic fibroblasts, and furthermore show increased M2-like macrophages and regulatory T-cells. Contrastingly, patients with ‘normal’ stroma show M1-like recruitment, elevated effector and exhausted T-cells. To aid interoperability of future studies, we provide a pretrained cell type classifier and an atlas of subtype-based signaling factors that we also validate in mouse data. Ultimately, this work leverages the heterogeneity among single-cell studies to create a comprehensive view of the orchestra of signaling interactions governing PDAC.

Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

“…Complementarily, we here show that JUNB/AP1 acts as a counterpart to promote a favorable CLA phenotypic identity in PDAC. Of note, JUNB/AP1-mediated transcriptional programs can also confer tumor-promoting functions in other cancer types [39][40][41] ; JUN/AP1 TFs are highly context dependent and may co-operate for target gene transcription [41][42][43] or oppose one another 44 Altogether, this string of insights provides a potential mechanistic foundation for several recent studies that showed a high degree of heterogeneity in the neoplastic and stromal immune compartments in human PDAC, including hybrid/intermediate/coexpressor CLA/BL subtype states that exist in naive and therapy-treated PDAC tumors [10][11][12][13][14][15][16]20,36,37 . We propose that extrinsic regional TNF-α plays an essential role in destabilizing CLA neoplastic cell identity by promoting BL cJUN/AP1-mediated transcriptional programs.…”

“…Here, we investigated the role of neoplastic AP1-mediated epigenetic and transcriptional programs in shaping the local inflammatory TiME, which in turn is critical for intratumoral subtype plasticity and PDAC aggressiveness [10][11][12][13][14][15]20,36,37 . We report that AP1 transcription factors (JUNB/AP1 vs. cJUN/AP1) hold a dichotomous role in maintaining both the plasticity and stability of CLA and BL neoplastic cells via intrinsic epigenetic and transcriptional regulation of lineage gene expression as well as extrinsic inflammatory processes.…”

“…However, it has become clear that the CLA and BL subtypes are not discrete states of individual PDAC tumors, but rather co-exist and contribute to significant intratumoral heterogeneity that is poorly understood. Multi-scale transcriptomic and imaging-based profiling has revealed a widespread co-existence of CLA and BL subtypes within PDAC patient tumors, as well as hybrid/co-expressor states that are implicated as transition mechanism between the subtype extremes [10][11][12][13][14][15] , emphasizing the complex tumor cell plasticity. Moreover, the extent of subtype co-existence increases in advanced disease, especially in metastatic samples 13,16,17 .…”

E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma

“…Previous reports showed that high expression of mainly E2F1 is predictive of a poor clinical outcome in PDAC patients (38, 39), while our analysis of E2F gene expression in PDAC tissue showed that low E2F8 expression was associated with poor disesease specific patient survival. Interestingly, E2F8 expression is mainly detected in the immunogenic PDAC subtype (40) and correlates with all the signature genes of the classical subtype (24, 41) but not with the genes linked to the basal subtype. These observations suggest that the low E2F8 expressing group in our survival group may identify patients with basal PDAC which have a much shorter DSS rate, while patients with classical PDAC have moderate to high E2F8 expression.…”

Expression of gemcitabine metabolizing enzymes and stromal components reveal complexities of preclinical pancreatic cancer models for therapeutic testing

“…Log2 expression data was extracted from Maurer et al [ 18 ], Oh et al [ 19 ] and Moffitt et al [ 5 ] with R2 Genomics ( https://hgserver1.amc.nl/cgi-bin/r2/main.cgi?open_page=login ) and exported into GraphPad Prism (v7.03).…”