Abstract B068: Human pancreatic cancer single cell atlas reveals association of CXCL10 positive fibroblasts and basal subtype tumor cells
Authors: Ian M Loveless, Samantha B Kempt, Yuesong Wu, Daniel J Salas-Escabillas, Kailee Hartway, Madison George, Yetunde Makinwa, Thais Stockdale, Samuel D Zwernik, Kendyll Gartrelle, Rohit G Reddy, Daniel Long, Allison Wombell, Julie M Clark, Albert M Levin, David Kwon, Ling Huang, Ralph Francescone, Débora B Vendramini-Costa, Ben Stanger, Adam Alessio, Andrew M Waters, Yuehua Cui, Brian Theisen, Howard C Crawford, Nina G Steele
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit severe resistance to standard of care treatments and have significantly worse overall survival, compared to patients with classical subtype enriched tumors. It is therefore important to develop resources that allow identification of novel targets in a statistically rigorous way to overcome therapeutic challenges. Here we compiled a single cell RNA sequencing (scRNAseq) atlas of the human pancreas with 229 individual patient samples, aggregated from raw data obtained from published studies. We mapped cell-type specific scRNAseq gene signatures in newly generated (n=12) and existing (n=13) spatial transcriptomics (ST) data from PDAC samples. Analysis of tumor cells from our scRNAseq atlas revealed nine transcriptionally distinct populations, two of which strongly align with a basal gene signature, correlating with worse overall survival in PDAC bulk RNAseq datasets. Deconvolution showed one of the basal populations identified to be the predominant tumor subtype in non- dissociated ST tissues and in vitro tumor cell and organoid PDAC lines. In bulk RNAseq datasets, we uncovered that myofibroblasts (myFb) expressing CXCL10 consistently correlated with both basal subtypes and were found near basal tumor cells using immunostaining. We also identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, further suggesting a relationship between these cell types in PDAC tumor microenvironment (TME). Overall, we show that our newly built scRNAseq atlas, containing over 700,000 cells, integrated with ST data is a powerful resource, given that it corroborates numerous PDAC TME observations in the literature, with increased statistical power. Moreover, we uncovered a novel association between CXCL10+ myFb and basal tumor cells, underscoring the presence of unique spatial niches in PDAC that should be explored for the development of targeted therapies for this dismal disease. Citation Format: Ian M Loveless, Samantha B Kempt, Yuesong Wu, Daniel J Salas-Escabillas, Kailee Hartway, Madison George, Yetunde Makinwa, Thais Stockdale, Samuel D Zwernik, Kendyll Gartrelle, Rohit G Reddy, Daniel Long, Allison Wombell, Julie M Clark, Albert M Levin, David Kwon, Ling Huang, Ralph Francescone, Débora B Vendramini-Costa, Ben Stanger, Adam Alessio, Andrew M Waters, Yuehua Cui, Brian Theisen, Howard C Crawford, Nina G Steele. Human pancreatic cancer single cell atlas reveals association of CXCL10 positive fibroblasts and basal subtype tumor cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B068.