The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma

Abstract

Intratumour heterogeneity (ITH) has become an important focus of cancer research in recent years. ITH describes the cellular variation that enables tumour evolution, including tumour progression, metastasis and resistance to treatment. The selection and expansion of genetically distinct treatment-resistant cancer cell clones provides one explanation for treatment failure. However, tumour cell variation need not be genetically encoded. In pancreatic ductal adenocarcinoma (PDAC) in particular, the complex tumour microenvironment as well as crosstalk between tumour and stromal cells result in exceptionally variable tumour cell phenotypes that are also highly adaptable. In this review we discuss four different types of phenotypic heterogeneity within PDAC, from morphological to metabolic heterogeneity. We suggest that these different types of ITH are not independent, but, rather, can inform one another. Lastly, we highlight recent findings that suggest how therapeutic efforts may halt PDAC progression by constraining cellular heterogeneity.

Uncovering the hidden threat: single-organoid analysis reveals clinically relevant treatment-resistant and invasive subclones in pancreatic cancer

“…PDAC070). Nonetheless, even though the NDR shows an overall better drug screening performance (can distinct cytostatic from cytotoxic responses and shows conformity with the transcriptional signatures) compared to the current gold standards, we still did not capture the full story of PDAC as heterogenous and immensely complex/adaptive disease 37,38 . Therefore, we integrated a novel singleorganoid readout that is able to dynamically monitor this complexity and response heterogeneity.…”

Combined CT and serum CA19-9 for stratifying risk for progression in patients with locally advanced pancreatic cancer receiving intraoperative radiotherapy

“…In contrast, iso-attenuated lesions or lesions with enhancement closer to surrounding pancreatic parenchyma are probably well-or moderately-differentiated, with more residual alveolar cells and closer to normal pancreatic tissue (33). Furthermore, PDAC appearing as hypo-attenuated may be associated with an extensive desmoplastic stromal reaction, resulting in decreased blood flow and insufficiency of blood supply (34). Moreover, dense fibrotic deposition also causes hypoxia, which is an important cause of resistance to radiotherapy (35, 36 PDACs corresponded more often with aggressive histologic grade, larger tumor size, less extensive fibrous stromal fraction, and poor disease-free survival and OS (16).…”

Are There Specific Cancer Stem Cell Markers?

“…While general considerations mentioned above suggest the existence of definitive markers identifying cancer cell subpopulations including CSCs, in practice the picture is often rather unclear. For example, in pancreatic ductal adenocarcinoma, several markers have been reported to identify CSCs, including CD44, CD133, c-MET, ALDH1, Dclk1, CD90, Msi1, Msi2, and CD9, with the functional relationship between these cellular subsets being unresolved ( 7 ). Similar differences in CSC characterization have also been seen in other tumor types.…”