Abstract
Extracting Mechanisms of Cell Cross Talk in Pancreatic Cancer Using Big Data
- Purpose: Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard of care treatments and have significantly worse overall survival (OS) compared to patients with classical subtype enriched tumors. It is important to develop resources that identify novel putative targets in a statistically rigorous way to overcome therapeutic challenges.
- Experimental Design: We compiled a single cell RNA sequencing (scRNAseq) atlas of the human pancreas with 229 patient samples, aggregated from publicly available raw data. We mapped cell-type specific scRNAseq gene signatures in bulk RNAseq (n=744) and spatial transcriptomics (ST) (n=22).
- Results: Analysis of tumor cells from our scRNAseq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse OS in bulk RNAseq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in non-dissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer associated fibroblasts (CAFs) with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in PDAC tumor microenvironment (TME).
- Conclusions: We show that our scRNAseq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ CAFs and basal tumor cells that could be explored for future targeted therapies.
Speaker
Nina Steele
Assistant Professor, Cancer Biology
Wayne State University
Nina Steele did her undergraduate training at Xavier University in Biology, then graduate work at University of Cincinnati in Physiology and Systems Biology. Her postdoc work was on Hedgehog signaling in pancreatic cancer at the University of Michigan. She published a Nature Cancer paper during her time there that has been cited over 350 times. Dr. Nina Steele is currently an Assistant Scientist at Henry Ford Hospital and is appointed in the Department of Pathology at Wayne State University and the Department of Pharm Tox at Michigan State University. She is the recipient of a K99/R00 for her work on the tumor microenvironment of pancreatic ductal adenocarcinoma. She recently published the lab's first paper in the journal Clinical Cancer Research, which details to date the world's largest single cell RNA sequencing atlas of the human pancreas. She is also the co-PI recipient of a prestigious Lustgarten Foundation award on her work on racial disparities in pancreatic cancer.