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Skorupan et al. J Cancer Metastasis Treat 2023;9:5 https://dx.doi.org/10.20517/2394-4722.2022.106 Page 7 of 26

Figure 2. Molecular characteristics of ASCP and PACC. Left- Adenosquamous carcinoma of the pancreas (ASCP) is characterized by
KRAS, MYC and TP63ΔN activation. Epigenetic changes cause loss of expression of chromatin-modifying genes such as KDM6A and
KMT2C/D as well as molecular determinants of endoderm fate leading to expression of squamous programs. Many of the usual
mutations present in PDAC also occur in ASCP. Like PDAC, ASCP is known to have a dense and prolific desmoplastic stroma that is
enriched in immunosuppressive immune cells. Right- Pancreatic acinar cell carcinoma (PACC) is not defined by changes in single
genes. Mutational signatures suggest that impairment of the DNA damage repair system is frequent in this tumor type. Methylation
and copy number changes cause downregulation of several tumor suppressors at the protein level. Activating BRAF/RAF1 mutations
and fusion products have been frequently observed. The tumor is highly cellular with little stroma, extensive vasculature, and limited
immune cell infiltration. Created with BioRender.com.

The upstream genetic and epigenetic changes required to stimulate TP63ΔN expression are slowly becoming
clearer. Upregulation of TP63ΔN can result from inactivating mutation or loss of the histone demethylase
[74]
KDM6A, a genomic change that has been observed in ASCP and PDAC with SF/SD . Recently, it was
shown that loss of HNF1A, a homeodomain transcriptional regulator that recruits KDM6A to genomic
binding sites, can phenocopy KDM6A loss and produce a sarcomatoid tumor morphology in conjunction
with Kras mutation in mouse pancreas . Trans-differentiation to a squamous morphology appears to
[75]
require concomitant loss of endodermal cell fate determinants such as GATA6, although the loss of GATA6
alone is insufficient to drive the squamous program . It is important to note that KDM6A loss is not
[76]
ubiquitous in squamous trans-differentiated pancreatic cancers, and therefore one might hypothesize that
other chromatin regulatory genes found to be mutated in ASCP and PDAC with SF/SD (such as ARID1A,
KMT2C, KMT2D, SMARCA2, ARID2, ASXL2, TET1 and MSL2 [39,62] ) may also lead to upregulation of TP63Δ
N.

Summary of ASCP histology and molecular pathology
In conclusion, ASCP is an extreme form of the basal/squamous subtype of PDAC that contains both
glandular and squamous regions. Squamous differentiation is primarily driven by epigenetic
reprogramming through loss of chromatin regulatory elements and endodermal cell fate determinants, with