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David. J Cancer Metastasis Treat 2022;8:32 https://dx.doi.org/10.20517/2394-4722.2022.71 Page 9 of 12

[71]
member of the p53 family , and it functions as a lineage determinant in the development of the normal
[72]
squamous lineage . An isoform encoded by the TP63 gene lacking a portion of the full-length N-terminus
(ΔNp63) is also an indispensable part of the transcriptional program of squamous cell carcinomas derived
from skin, lung, esophagus, and head and neck [73-75] . While it is not expressed in the normal pancreas,
expression of the ΔNp63 isoform is abundant in tumors of the basal-like subtype . In PDA with squamous
[17]
characteristics that form upon KDM6A knockout in the pancreas, an enhancer at the Trp63 locus activates
ΔNp63 expression .
[38]

Functional experiments with ΔNp63 have now made it clear that it is an important master regulator of the
basal-like subtype. Using loss- and gain-of-function experiments in human cell lines, it was demonstrated
that ΔNp63 expression was necessary and sufficient to confer squamous-like gene expression on PDA
cells [76,77] . Activation of the squamous program by ΔNp63 overexpression in classical cells conferred the cells
with increased migratory capacity in vitro and enhanced growth in vivo, consistent with the worse prognosis
[76]
associated with basal-like tumors .

In addition to ΔNp63, the Hedgehog (Hh) signaling TF GLI2 also contributes to the basal-like state . The
[78]
activation of this TF in PDA cells appears independent of Hh ligands and correlates strongly with EMT-
high basal-like characteristics in PDA cell lines. As expected of a subtype determinant, GLI2 overexpression
was sufficient to confer basal-like properties on classical cell lines, while its depletion shifted basal-like cells
towards classical attributes. The enforcement of the basal-like state by GLI2 was at least partly dependent on
one of its target genes, the inflammatory secreted factor osteopontin (OPN). Depletion of OPN reversed the
basal-like phenotype of PDA cells, while supplying exogenous OPN could confer basal-like properties on
others . This suggests that cancer cells that adopt a basal-like phenotype may induce others to follow suit
[49]
through secreted signals such as OPN.

PERSPECTIVE
The importance of PDA transcriptional subtypes to the biology of the disease and the outcome of patients
has gained recognition over the past several years, and it remains a highly active area of investigation. The
distinct biology of the two subtypes, highlighted by work uncovering distinct gene expression programs
governed by TFs associated with each state, suggests that each subtype will have distinct dependencies.
Based on the work discussed above, these dependencies could be metabolic, signaling, or immune-related,
and it appears likely that additional specific dependencies will be revealed for each subtype.

While subtype-specific dependencies are of interest, it will be even more important to find shared
requirements that unite all PDA cells. KRAS signaling appears to represent a unifying PDA dependency (at
least in 90% of PDA tumors with KRAS mutations), although some details remain to be cleared up about the
role of KRAS in each subtype. As discussed, gains in KRAS signaling are associated with a tendency towards
a basal-like phenotype, although it is unclear what, if anything, connects gains in KRAS signaling with the
more aggressive subtype. In apparent discord with that data, evidence has also been presented indicating
that basal-like cells are more resistant to KRAS depletion . Deciphering the role of KRAS in shaping and
[78]
then maintaining PDA subtypes will be of great interest to future studies.

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.