Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity
Year: 2022
Type: article
Study design: Observational Study
Abstract: Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC. SIGNIFICANCE: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.
Source: Cancer Research
Authors: Hannah L. Williams, Andressa Dias Costa, Jinming Zhang, Srivatsan Raghavan, Peter S. Winter, Kevin S. Kapner, Scott P. Ginebaugh, Sara A. Väyrynen, Juha P. Väyrynen, Chen Yuan, Andrew W. Navia, Junning Wang, Annan Yang, Timothy L. Bosse, Radha L. Kalekar, Kristen E. Lowder, Mai Chan Lau, Dalia Elganainy, Vicente Morales-Oyarvide, Douglas A. Rubinson, Harshabad Singh, Kimberly Perez, James M. Cleary, Thomas E. Clancy, Jiping Wang, Joseph D. Mancias, Lauren K. Brais, Emma R. Hill, Margaret M. Kozak, David C. Linehan, Richard F. Dunne, Daniel T. Chang, Albert C. Koong, Aram F. Hezel, William C. Hahn, Alex K. Shalek, Andrew J. Aguirre, Jonathan A. Nowak, Brian M. Wolpin
Institutions: Brigham and Women's Hospital, Harvard University, Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center, Broad Institute, Ragon Institute of MGH, MIT and Harvard, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Oulu University Hospital, University of Oulu, Stanford Cancer Institute, University of Rochester Medicine, University of Rochester, The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1047483779, Dana Farber/ Harvard Cancer Center SPORE in Gastrointestinal Cancer, G2883192542, G3045899018, G3101773556, G3401812931, G6682102338, Development and implementation of multiplex methods to understand the biology and heterogeneity of patient-derived cancer models, G9000050131, G9000160112, G9000176325, G9000207199, Leveraging Novel Randomized Clinical Trials of Vitamin D Supplementation in Patients with Colorectal Cancer: Impact on Survival and Anti-Tumor Immunity, Environmental Agents as Modulators of Disease Processes, Altered metabolism and machine learning for pancreatic cancer early detection, Mechanisms of response and resistance to KRAS inhibition in pancreatic cancer
OpenAlex ID: W4310639010