Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.
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Moffitt and colleagues used a virtual dissection strategy to computationally subtract stromal and immune transcriptional background from bulk RNA sequencing and identified classical and basal-like tumor subtypes plus normal and activated stromal subtypes.
“Moffit and colleagues devised a “virtual dissection strategy” to computationally subtract the transcriptional background imposed by stromal and immune cells from bulk-RNA sequencing signatures131. Using this approach, they identified two subtypes of PDAC tumors, termed “classical” and “basal-like”, in addition to two stromal subtypes termed “normal stroma” and “activated stroma”.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [131]
The dichotomous Moffitt classification schema of "basal-like" and "classical" subtypes was initially established using bulk RNA sequencing strategies applied to human tumor samples.
“The dichotomous Moffitt classification schema of “basal-like” and “classical” subtypes was initially established using bulk RNA sequencing strategies applied to human tumor samples (Moffitt 2015)36.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as Moffitt 2015
The dichotomous Moffitt classification schema of "basal-like" and "classical" subtypes was initially established using bulk RNA sequencing strategies applied to human tumor samples.
“The dichotomous Moffitt classification schema of “basal-like” and “classical” subtypes was initially established using bulk RNA sequencing strategies applied to human tumor samples (Moffitt 2015)36.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as [36]
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- Authors
- Moffitt, R. A., Marayati, R., Flate, E. L., Volmar, K. E., Loeza, S. G. H., Hoadley, K. A., Rashid, N. U., Williams, L. A., Eaton, S. C., Chung, A. H., Smyla, J. K., Anderson, J. M., Kim, H. J., Bentrem, D. J., Talamonti, M. S., Iacobuzio-Donahue, C. A., Hollingsworth, M. A., & Yeh, J. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Nebraska–Lincoln (US)
- Northwestern University (US)
- Corresponding author
- Yeh, Jen Jen
- ORCID
- Venue
- Nature Genetics
- Published
- 2015-09-07
- Volume
- 47
- Issue
- 10
- Pages
- 1168-1178
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4912058
- OpenAlex
- W1497915798
- Cited by
- 2,194
- References
- 63
- Citations by year
- 2026: 227 · 2025: 237 · 2024: 236 · 2023: 252 · 2022: 256 · 2021: 298 · 2020: 223 · 2019: 168 · 2018: 124 · 2017: 96 · 2016: 65 · 2015: 9
- FWCI
- 42.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (T32CA009156, R01CA140424, P30CA060553)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK034897, P30DK034987)
- National Institute of Environmental Health Sciences (P30ES010126)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- pancreatic ductal adenocarcinoma, tumor stroma, tumor subtypes, gene expression signatures, blind source separation, basal-like subtype, prognostic subtypes, metastatic pancreatic cancer, molecular classification
- MeSH terms
- Adenocarcinoma, Animals, Female, Humans, Male, Pancreatic Neoplasms, Gene Expression, Stromal Cells, Genetic Heterogeneity, Carcinoma, Pancreatic Ductal, Heterografts
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