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Page 2 of 12 David. J Cancer Metastasis Treat 2022;8:32 https://dx.doi.org/10.20517/2394-4722.2022.71

PDA patients is due in part to the intrinsically aggressive nature of the disease.

Potentially contributing to this clinical intractability is an emerging hallmark of pancreatic cancer, plasticity
- the ability of tumor cells to adopt new identities in response to specific signals or through natural
selection. A high degree of plasticity is already evident around the time of tumor initiation, when identity
shifts can play a critical role in the emergence of pancreatic intraepithelial neoplasia (PanIN), the most
[3]
common precursor to PDA . Approximately 90% of PDA tumors are driven by oncogenic KRAS
mutations , and despite the ductal histology of PDA tumors, acinar cells have proven to be more amenable
[4]
[5]
to KRAS-mediated transformation than ductal cells in mouse models . Activation of mutant KRAS,
combined with inflammation, converts acinar cells into duct-like cells through a process known as acinar-
[6-8]
[9]
to-ductal metaplasia (ADM) , followed by the emergence of PanINs . The ease with which acinar cells are
transformed is partly due to the fact that the duct-like cells that emerge during ADM harbor a proto-
oncogenic transcriptional program that is locked into place by KRAS mutations . It is now clear that all
[10]
major epithelial cell types of the pancreas (acinar, ductal, and endocrine) can give rise to PDA through a
combination of KRAS activation, tumor suppressor gene inactivation, and inflammation [11-14] .

While the plasticity exhibited by normal pancreatic cells in the face of oncogenic and inflammatory insults
is relatively well understood, recent studies have suggested another form of plasticity that exists among
cancer cells after the emergence of invasive carcinoma. For over a decade, it has been clear that PDA tumors
can be separated into distinct transcriptomic subtypes . More recent evidence, discussed in detail in this
[15]
review, argues that subtypes are not static; tumor cells can readily transit between these transcriptional
states. This form of plasticity has important ramifications for tumor progression and patient outcomes.

TRANSCRIPTIONAL SUBTYPES OF PANCREATIC CANCER
Despite a relatively homogeneous landscape of driver mutations (i.e., KRAS mutations), pancreatic cancer
exhibits important inter- and intra-tumoral transcriptomic heterogeneity. This heterogeneity has important
implications for the biology of the disease.

Over the past decade, several studies developed classification systems based on gene expression profiling
across tumors. The first such study, performed by Collisson et al. used microarray data from microdissected
PDA tumors, arriving at three distinct subtypes: classical, quasi-mesenchymal (QM-PDA), and exocrine-
[15]
like . Mouse and human cell lines with gene expression profiles mirroring the classical and QM-PDA but
not the exocrine-like tumors could be established, raising the possibility that the exocrine subtype reflected
contamination from surrounding normal pancreatic tissue. Patients with QM-PDA tumors fared more
poorly than those with classical tumors, the first indication that tumor transcriptional subtypes impact the
biological properties of the cancer. Additionally, classical and QM-PDA cells differed in their response to
chemotherapy drugs, while classical cells displayed a higher dependency on continued mutant KRAS
expression.

The abundant stroma of PDA and the potential for contaminating normal tissue presents a confounding
issue for the identification of cancer-specific gene expression signatures and the precise assignment of
tumor subtypes. A second study refined these subtype definitions by employing a bioinformatic technique
termed “digital microdissection” to untangle gene expression in the tumor epithelium from that in the
stroma and surrounding normal tissue . Using this approach, these authors identified two subtypes,
[16]
classical and basal-like. The exemplar genes defined by Moffitt et al. in classical tumors corresponded well
to the classical signature defined by Collisson et al. confirming the existence of that subtype. Moffitt et al.
named the basal-like subtype due to the shared expression of keratins present in the basal subtype of other