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Figure 3. Schematic presentation of PCSC properties and their contribution to EMT, tumor metastasis and recurrence, chemoresistance,
and apoptosis resistance. Potential CSC markers and signaling pathways in PCSCs and activation of several signaling pathways in the self-
renewal, maintenance, and tumor recurrence in PDAC are also shown. PCSC: pancreatic cancer stem cell; EMT: epithelial-mesenchymal
transition

Signaling pathways in PCSCs
Various signaling pathways are altered in PCSCs and EMT cells including Hedgehog, Notch, Wnt, NF-κB,
and AKT [Figure 3]. Among these, Hedgehog, Notch, and Wnt play particularly important roles in
[51]
PCSCs . These signaling pathways are critical regulators of PCSC self-renewal, tumor growth, invasion,
metastasis, and therapy resistance [16,40,80,81] . Furthermore, miRNAs play a significant role in the regulation of
PCSCs [82,83] .

Notch signaling regulates cell proliferation, survival, apoptosis, and the differentiation of various cancers
including pancreatic cancer cells and PCSCs as well as promoting EMT by controlling some transcription
factors and growth factors including Snail, Slug, and TGF-β. Notch targets many genes which play critical
roles in the development and progression of human malignancies [84-86] . Several studies have demonstrated
that resistance to chemotherapy in PCSCs is linked to the active Notch signaling pathway [63,87,88] .

Another self-renewal pathway in PCSCs is Hedgehog signaling, which is involved in tumor initiation,
progression, and metastasis [63,89,90] . The three hedgehog genes include Sonic hedgehog (Shh), Indian