Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma

Abstract

Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials.

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

“…Conversely, differentially underexpressed genes were enriched for the classical-like signature (p = 4.46 x 10 -24 ), including the hallmark transcription factor GATA6 (7,9,78,80) (Figure 2C). Consistently, human PDAC cell lines become enriched for the basal-like subtype after FOLFIRINOX (14,81). These observations could reflect either cell state changes following CRT, differential sensitivity to CRT, or both.…”

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

“…[2][3][4][5][6] In PDAC, bulk transcriptional profiling has defined two major transcriptional subtypes, basal-like/squamous (hereafter referred to as "basal") and classical, where the former is associated with worse prognosis and greater treatment resistance. [3][4][5][7][8][9][10][11][12][13][14] However, classification based on bulk expression profiling can obscure clinically relevant cellular attributes because it reduces signals from multiple cell types to a single, whole sample average. In reality, PDAC tumors, like many other cancers, are complex multicellular ecosystems shaped by both malignant and microenvironmental features.…”

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

“…Single cell RNA sequencing [15] and immunohistochemistry [18] of PDAC revealed intra-tumor heterogeneity where both types of cells (basal-like and classical) frequently co-exist. RNA profiling of multiple regions or multiple lesions from the same patient also demonstrated intra-tumor heterogeneity of the transformed epithelial compartment [4].…”