Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy

By E. Collisson, A. Sadanandam, P. Olson, W. J. Gibb, Morgan L. Truitt, Shenda Gu, J. Cooc, Jennifer Weinkle, Grace E. Kim, L. Jakkula and 8 more. Nature Medicine, 2011

1,735 citations recorded by the source corpus.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast and lung cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.

Subfields: Cancer Research, Epidemiology, Oncology

View Paper: https://www.semanticscholar.org/paper/ca190c04e4cd4fe7a575e5b524d8f01c2f5a75a8

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Citations in the corpus

EMT subtype influences epithelial plasticity and mode of cell migration (2018, methodology): “In all cases, C-EMT tumors were strongly associated with poorly-differentiated transcriptional subtypes (quasi-mesenchymal (Collisson et al., 2011), squamous (Bailey et al.”
Cancer heterogeneity—a multifaceted view (2013, positive): “Similarly, different pancreatic adenocarcinoma subtypes show differential response to anti-EGFR treatment despite the presence of KRAS mutations [76].”
Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy (2014, positive): “2 were derived from PDA inKras; Trp53; p48-Cremice or Kras; Ink4a/Arf; p48-Cremice (Bardeesy et al., 2006; Collisson et al., 2011) and cultured as described previously (Collisson et al.”
Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (2014, positive): “Interestingly, our findings in the mouse model are reinforced by observation in human PDAC showing a prominence of similar transcriptional programs in the quasimesenchymal subset (QM subset) of pancreatic cancers, which are notable for lower dependency on oncogenic KRAS relative to other PDAC subset”
Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression and improves chemotherapeutic responses (2012, neutral): “Tg (17, 18) and p48-CRE/LSL-KrasG12D/INK4a (18, 19) mice, respectively.”
CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T Cell Checkpoint Immunotherapy in Pancreatic Cancer Models (2014, neutral): “Additional details on PLX3397 can be found in theMaterials and Methods section and published elsewhere (16, 17, 18, 21).”
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. (2016, methodology): “coli as truncated (1-169), hexahistidine-tagged forms as described by Ostrem and colleagues ( 6 ).”