Most detailed spatial atlas yet for mapping the pancreatic tumor microenvironment
A spatial atlas maps pancreatic tumor cell identity and location, illuminating potential treatment pathways for pancreatic ductal adenocarcinoma.
An international collaboration led by researchers at the University of Birmingham, University Hospitals Birmingham NHS Foundation Trust (both UK) and Bristol Myers Squibb (NJ, USA) has developed the most detailed spatial atlas of pancreatic cancer tissue to date, to gain a deeper insight into the complex organization and cellular identities present in pancreatic ductal adenocarcinoma (PDAC) tumors.
PDAC is the most common type of exocrine pancreatic cancer, with an average 5-year survival rate of less than 10%, which is due in large part to the cancer’s complexity. It is characterized by its heterogeneity, low tumor purity and complex tumor microenvironment (TME) architecture, all of which restrict researchers’ abilities to identify shared TME features within patients and across patient populations that could aid the development of effective treatments.
To overcome this significant hurdle in our understanding of PDAC, researchers have used a combination of approaches to achieve a spatial–molecular map of untreated PDAC primary tumors. They leveraged two complementary spatial genomics approaches, spatial transcriptomics and spatial molecular imaging, to determine cellular identity and location within formalin-fixed, paraffin-embedded tumor resections from 39 individuals with PDAC, compared to human tumor cell lines and mouse models of the disease.
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Within the 39 tissue samples, they identified five distinct malignant cellular subtypes spanning the classical-to-basal spectrum and two pre-malignant ductal and intraepithelial neoplasia subtypes. Each subtype displayed distinct regulators, stromal neighborhoods, microenvironment, extracellular matrix and histology, which also corresponded to multiple immunosuppressive and therapeutic-resistance mechanisms.
One subtype in particular may drive tumor growth, showing high proliferation marked by significant cell-division activity, while another was identified as a new intermediate subtype – both adding to our understanding of pancreatic cancer progression and tumor organization.
“This spatial atlas is expected to serve as a foundational resource for the research community and may accelerate the development of treatments for a disease that has long resisted progress,” commented co-senior author Shivan Sivakumar (University of Birmingham and University Hospitals Birmingham NHS Foundation Trust).
“By integrating spatial biology with functional genetic screening, we have created a roadmap for discovering therapies that target pancreatic cancer more effectively – especially combination treatments designed to disrupt both cancer cells and the environments that protect them.”