Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity

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

doi:10.1158/0008-5472.CAN-22-3050

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Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity

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Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity

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, …

Cancer research (Chicago, Ill.), Vol.83(3), pp.441-455

02/03/2023

DOI: 10.1158/0008-5472.CAN-22-3050

PMCID: PMC10548885

PMID: 36459568

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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. 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.

Phenotype

RNA

Carcinoma, Pancreatic Ductal - genetics

Carcinoma, Pancreatic Ductal - pathology

Claudins

Gene Expression Regulation, Neoplastic

Humans

Pancreatic Neoplasms - pathology

Prognosis

Details

Title: Subtitle: Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity
Creators: Hannah L Williams - Dana-Farber Cancer Institute
Andressa Dias Costa - Dana-Farber Cancer Institute
Jinming Zhang - Dana-Farber Cancer Institute
Srivatsan Raghavan - Broad Institute
Peter S Winter - Massachusetts Institute of Technology
Kevin S Kapner - Dana-Farber Cancer Institute
Scott P Ginebaugh - Dana-Farber Cancer Institute
Sara A Väyrynen - Dana-Farber Cancer Institute
Juha P Väyrynen - Oulu University Hospital
Chen Yuan - Dana-Farber Cancer Institute
Andrew W Navia - Massachusetts Institute of Technology
Junning Wang - Broad Institute
Annan Yang - Broad Institute
Timothy L Bosse - Broad Institute
Radha L Kalekar - Broad Institute
Kristen E Lowder - Broad Institute
Mai Chan Lau - Dana-Farber Cancer Institute
Dalia Elganainy - Dana-Farber Cancer Institute
Vicente Morales-Oyarvide - Dana-Farber Cancer Institute
Douglas A Rubinson - Dana-Farber Cancer Institute
Harshabad Singh - Dana-Farber Cancer Institute
Kimberly Perez - Dana-Farber Cancer Institute
James M Cleary - Dana-Farber Cancer Institute
Thomas E Clancy - Brigham and Women's Hospital
Jiping Wang - Brigham and Women's Hospital
Joseph D Mancias - Brigham and Women's Hospital
Lauren K Brais - Dana-Farber Cancer Institute
Emma R Hill - Dana-Farber Cancer Institute
Margaret M Kozak - Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California
David C Linehan - University of Rochester Medical Center
Richard F Dunne - University of Rochester Medical Center
Daniel T Chang - Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California
Albert C Koong - The University of Texas MD Anderson Cancer Center
Aram F Hezel - University of Rochester Medical Center
William C Hahn - Broad Institute
Alex K Shalek - Massachusetts Institute of Technology
Andrew J Aguirre - Broad Institute
Jonathan A Nowak - Brigham and Women's Hospital
Brian M Wolpin - Dana-Farber Cancer Institute
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.83(3), pp.441-455
DOI: 10.1158/0008-5472.CAN-22-3050
PMID: 36459568
PMCID: PMC10548885
NLM abbreviation: Cancer Res
eISSN: 1538-7445
Grant note: R01 CA169141 / National Cancer Institute (NCI) R35 CA197735 / National Cancer Institute (NCI) R01 CA248857 / National Cancer Institute (NCI) PST-15-18 / Damon Runyon Cancer Research Foundation (DRCRF) U01 CA250549 / National Cancer Institute (NCI) P50 CA127003 / National Cancer Institute (NCI) R01 CA205406 / National Cancer Institute (NCI) U01 CA210171 / National Cancer Institute (NCI)
Language: English
Date published: 02/03/2023
Academic Unit: Radiation Oncology
Record Identifier: 9984364760002771

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