Tumor cell heterogeneity and its transcriptional bases in pancreatic cancer: a tale of two cell types and their many variants

Abstract

Pancreatic ductal adenocarcinoma (PDAC), one of the most highly lethal tumors, is characterized by complex histology, with a massive fibrotic stroma in which both pseudo‐glandular structures and compact nests of abnormally differentiated tumor cells are embedded, in different proportions and with different mutual relationships in space. This complexity and the heterogeneity of the tumor component have hindered the development of a broadly accepted, clinically actionable classification of PDACs, either on a morphological or a molecular basis. Here, we discuss evidence suggesting that such heterogeneity can to a large extent, albeit not exclusively, be traced back to two main classes of PDAC cells that commonly coexist in the same tumor: cells that maintained their ability to differentiate toward endodermal, mucin‐producing epithelia and epithelial cells unable to form glandular structures and instead characterized by various levels of squamous differentiation and the expression of mesenchymal lineage genes. The underlying gene regulatory networks and how they are controlled by distinct transcription factors, as well as the practical implications of these two different populations of tumor cells, are discussed.

Cancer evolution: Darwin and beyond

“…The notion that cancer cells can dynamically switch from one state to another in response to environmental stresses and therapeutic pressure without genomic alterations is gaining greater recognition (Pogrebniak & Curtis, 2018; Mills et al , 2019; Boumahdi & de Sauvage, 2020) (discussed in other reviews of this series by Milan et al , 2021). This phenomenon, termed cell plasticity, is characterised by a fundamental change in the biological properties of the cell occurring as a consequence of dynamic and reversible epigenetic and transcriptional changes (in sharp contrast to genetic alterations, which have binary and largely irreversible effects) (Calabrese et al , 2020).…”

Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

“…We envisage that the opposite effects of SFK on KRAS and YAP provide a flexible mechanism that enables PDAC cells to initiate EMT and metastasis when SFK/YAP signaling predominates and explain coexistence of different subtypes of PDAC in different locations of the same tumor. Indeed, well-differentiated and poorly differentiated (basal-like/squamous) PDAC cells coexist in variable proportions in most PDACs [82].…”

“…Additional analysis using physical or virtual separation of cell types within the tumors, is subdividing the two major subtypes of PDAC in additional subgroups [79,80]. Recent studies using singlecell and single-nucleus RNA-seq, as well as pancreatic organoids [81], support the notion that the classical and basal-like/squamous PDAC cells coexist in variable proportions in most PDACs (reviewed in [82] and references therein). Accordingly, recent studies showed coexistence of basal-like and classical subtypes within individual PDAC tumors [79,83].…”

“…Accordingly, recent studies showed coexistence of basal-like and classical subtypes within individual PDAC tumors [79,83]. It is important to emphasize that the molecular subtypes of PDAC are not associated with somatic mutations but appear linked to the function of distinct gene regulatory networks and epigenetic events [82]. Thus, the mechanisms driving the generation of PDAC subtypes remain incompletely understood and of importance, because switching basal subtype to classical subtype may provide a strategy to increase sensitivity of PDACs to available therapeutic interventions.…”

Overview and Future Perspectives on Tumor-Targeted Positron Emission Tomography and Fluorescence Imaging of Pancreatic Cancer in the Era of Neoadjuvant Therapy

“…Despite advances in surgical and systemic treatment, the 5-year overall survival (OS) rate remains approximately 10% [ 4 ]. This low survival rate is mostly caused by late detection of disease due to the late onset of symptoms [ 5 ]. Therefore, most patients are diagnosed with advanced stage disease, and only a minority (15–20%) of patients are eligible for treatment with curative intent [ 4 , 6 , 7 ].…”