Mechanistic insights into hepatic metastasis of pancreatic cancer: molecular perspectives

Introduction

Pancreatic cancer (PC) is one of the most aggressive malignant tumors. PC is divided into pancreatic head cancer, pancreatic body and tail cancer, and whole PC based on the site of occurrence. PC can be divided into pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, acinar cell carcinoma, small gland carcinoma, and small cell carcinoma based on pathology (1,2). In 2022, there were 511,000 new cases of PC and 467,000 deaths (3). Due to the lack of obvious symptoms in the early stage of PC, most patients are diagnosed at an advanced stage with metastasis, and the liver is the most important metastatic site. Therefore, understanding the recent research progress on hepatic metastasis of pancreatic cancer (HMPC) is particularly important. This study aims to establish a foundational reference framework to facilitate and inform subsequent research endeavors.

The role of key genes in HMPC

The expression or knockout of genes can affect the occurrence of HMPC (4,5). Yang et al. (6) found that HMGA1 may be an important marker for HMPC. The unique cellular subset composition and genetic profile of liver metastatic cancer may provide new insights into potential therapeutic targets and diagnostic markers for metastatic PC. Masugi et al. (7) that the gene deletion of Zeb1 leads to enhanced epithelial stability in cancer cells, promoting liver metastasis (LM) associated with PC. Xu et al. (8) found that HMGA1 may be an important marker for HMPC. The unique cellular subset composition and genetic profile of liver metastatic cancer may provide new insights into potential therapeutic targets and diagnostic markers for metastatic PC. Hermann et al. (9) found that men have a higher risk of HMPC compared to women, and it is speculated that it may be related to higher TIMP1 expression. D’Costa et al. (10) found that the gene deletion of Zeb1 leads to enhanced epithelial stability in cancer cells, promoting LM associated with PC. Carstens et al. (11) found that the gene deletion of Zeb1 leads to enhanced epithelial stability in cancer cells, promoting LM associated with PC. Zhang et al. (12) found that PC with a lack of STK11 is prone to LM. The LM inhibitor PDE4 roflumilast can inhibit the proliferation of tumor cells in STK11-deficient PC and inhibit LM. The pharmacological properties of roflumilast make it a potential targeted drug with clinical application prospects. The key initiating step in PDAC development is related to the activating mutation of the KRAS gene. KRAS is a membrane-bound GTPase that can transduce pro-survival and growth signals from cell surface receptors to the interior of the cell. Singh et al. (13) found that the phospholipid transporter PITPNC1 regulates KRAS overlapping transcription and controls the positioning of mTOR by enhancing the stability of MYC protein to inhibit autophagy, ultimately promoting PDAC LM. Entrialgo-Cadierno et al. (14) found that the phospholipid transporter PITPNC1 regulates KRAS overlapping transcription and controls the positioning of mTOR by enhancing the stability of MYC protein to inhibit autophagy, ultimately promoting PDAC LM. BBI608 is a promising targeted drug that may be used for clinical treatment in the future. In the future, it is necessary to continue exploring the role of the above genes in HMPC, which will, in turn, provide a basis for treatment. A study (15) reveals that mutant p53 promotes the invasion and metastasis of PC by regulating the neuropeptide Y (NPY) signaling pathway. Inhibition of this signaling axis significantly reduces the metastatic potential of cancer cells, thereby offering a novel therapeutic target for the treatment of PC. Emerging evidence (16) suggests that the interaction between glutathione S-transferase 1 (GSTP1) and p53 may suppress this phenomenon, warranting further in-depth investigation in future studies.

Immune microenvironment in HMPC

Tumor microenvironment (TME) is an important component of tumor tissue, containing tumor cells, immune cells, stromal cells, extracellular matrix (ECM), and various soluble molecules, playing an important role in the occurrence and development of tumors. In the TME of PC, tumor cells only account for a small part, and the rest is mostly stromal components, including a variety of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Treg), pancreatic stellate cells (PSCs), and cancer-associated fibroblasts (CAFs) (17-19). Due to the characteristics of the portal vein, various antigens transmitted to the liver through the portal vein tend to induce tolerance, both locally in the liver and systemically. This phenomenon is called portal vein tolerance, and its mechanism may involve antigen-presenting cells (APCs) participating in clonal deletion and the activation of Tregs, thereby mediating immunosuppression. The immunotolerant microenvironment leads to a decrease in the function, quantity, and distribution of cytotoxic cells, turning to promote immunosuppressive cells such as Tregs, ultimately promoting tumor metastasis and occurrence (20). Zhang et al. (21) found that there is a lack of tumor-immune cell interactions in metastatic tissue, which helps to form an immunosuppressive microenvironment. The liver microenvironment determines the metabolism of disseminated PC cells, thereby affecting the LM process (22). Li et al. (23) found that hyperglycemia exacerbates microenvironmental hypoxia and promotes HMPC. Chen et al. (24) found that exosomal tRF-GluCTC-0005 can upregulate WDR1 on one hand, and the N-terminal of WDR1 can directly bind to Yes-associated protein (YAP) protein, activating the Hippo pathway of hepatic stellate cells, and on the other hand, it can significantly recruit MDSCs in the liver, forming an immunosuppressive microenvironment, further promoting the LM of PDAC. Although this study detected the effect of tRF-GluCTC on interleukin (IL)-6 expression, the role of other tumor-related cytokines is still unclear. Hashimoto et al. (25) found that insulin-like growth factor (IGF)-Trap, a type I IGF receptor signal inhibitor, changes the local immunosuppressive tumor microenvironment (TME) in the liver, reduces the recruitment of MDSCs, reverses the polarization of innate immune cells, and ultimately inhibits HMPC. The drug, when used in combination with programmed cell death protein 1 (PD-1) antagonists, may have good effects. These research advances provide an essential scientific basis for understanding the immune microenvironment of PC liver metastases and provide new directions for future therapeutic strategies (Figure 1).

Figure 1 Metastatic pathways and hepatic immune microenvironment in HMPC (17,26). HMPC, hepatic metastasis of pancreatic cancer; MDSC, myeloid-derived suppressor cell.

The role of fibroblasts

CAFs are one of the most abundant cell types in pancreatic tumors (27). CAFs are a very challenging cell type because they have plasticity and stem cell-like characteristics, lack cell type-specific markers, and have environment-dependent effects. In addition, CAFs are closely related to ECM (28). Zheng et al. (29) found that laminin subunit alpha 4 (LAMA4) can activate CAFs and promote HMPC. However, the molecular mechanism of the interaction between LAMA4 and CAFs is not clear, necessitating further research to determine the potential mechanisms by which LAMA4 mediates the recruitment and activation of CAFs. Takesue et al. (30) discovered that in vitro experiments showed the formation of neutrophil extracellular traps (NETs) induced by PC cells, thereby promoting the formation of CAFs and ultimately promoting HMPC. Zhu et al. (31) found that co-delivery of cisplatin and rapamycin via multi-targeting liposomes can inhibit HMPC. Rapamycin reduces fibroblasts in the tumor center, enhancing drug penetration within the tumor tissue, while the combination of rapamycin and cisplatin can inhibit tumor cell proliferation, leading to apoptosis. CAFs are generally divided into two types: myofibroblast-like CAFs (myCAFs) that highly express α-smooth muscle actin (SMA) and fibroblast activation protein (FAP), and inflammatory CAFs (iCAFs) with secretory characteristics and functions in regulating inflammation (32,33). Pan et al. (34) found that tumor cells from PDAC that metastasize to the liver reprogram myCAFs into iCAFs, resulting in a more uniform distribution of CAFs in LM, a mechanism associated with IL-1β antibodies. Chang et al. (35) first discovered that PC cell-derived small extracellular vesicle ezrin (sEV-EZR) may activate fibroblasts to express α-SMA and PDGFRB through the signal transducers and activators of transcription 3 (STAT3) signaling pathways, thereby exacerbating PDAC metastasis. Activated fibroblasts and/or CAFs are inherently highly secretory, producing ECM and a large number of soluble factors, such as cytokines, chemokines, and growth factors (36). Pereira et al. (37) found that nidogen 2 (NID2) is mainly expressed by CAFs. Jiang et al. (38) discovered that keratin 7 (KRT7) promotes the LM of PC by enhancing the secretion of fibroblast growth factor 2 (FGF2), which activates fibroblasts and subsequently remodels the structure and function of the ECM. Wang et al. (39) revealed that CAF-derived MMP11 plays a pivotal role in promoting LM of PC. The downregulation of NID2 can inhibit LM of PDAC, suggesting that NID2 is an important target for LM of PDAC. Zhang et al. (40) found that baicalin may inhibit fibroblast growth factor binding protein 1 (FGFBP1)-mediated CAF infiltration, affecting the TME and ultimately inhibiting LM of PDAC. The role of fibroblasts in HMPC is multifaceted, including the construction of the TME, participation in immunosuppression, interaction with tumor cells, and promotion of tumor invasion and metastasis. These findings provide new targets and strategies for the treatment of PC (Figure 2).

Figure 2 Fibroblast related pathways. LAMA4, NET, sEV-EZR, FGFBP1 activate fibroblasts to promote α-SMA secretion, while rapa inhibits fibroblasts to inhibit α-SMA secretion (29,31,32,41,42). FGFBP1, fibroblast growth factor binding protein 1; LAMA4, laminin subunit alpha 4; NET, neutrophil extracellular trap; sEV-EZR, small extracellular vesicle ezrin; SMA, smooth muscle actin.

The role of neutrophils

Neutrophils are the most abundant type of white blood cells, accounting for 50–70% of white blood cells. NETs are extracellular structures formed by neutrophils, containing decondensed chromatin and chromatin-bound cytoplasmic and granular proteins (43). The induction of NETs in the pancreatic TME is closely related to the occurrence and development of PDAC (41). Kajioka et al. (44) found that the degradation of thrombomodulin can inhibit high-mobility group box 1 (HMGB1), thereby inhibiting the induction of NETs and ultimately inhibiting HMPC. Thrombomodulin may be a candidate drug that can eliminate the pro-metastatic conditions induced by surgical stress in NETs. The relationship between NETs and normal cells, as well as the impact of phorbol myristate acetate (PMA) and NETs on normal cells, requires further in-depth investigation. Wang et al. (45) found that metastatic PDAC tumors evade anti-tumor immunity by increasing the subset of neutrophils negative for P2RX1. Future immunotherapies can target this pathological subset of neutrophils. The NETs inhibitor DNase I can reverse HMPC. Bellomo et al. (46) found that after discontinuing chemotherapy, neutrophils are recruited to the liver by chemokine ligand 1 (CXCL1) and CXCL2 secreted by metastatic tumor cells. These neutrophils express growth arrest-specific 6 (Gas6), leading to the activation of the AXL receptor on tumor cells, promoting their regeneration. Disrupting neutrophil infiltration or inhibiting the Gas6/AXL signaling axis in combination with chemotherapy can inhibit the growth of metastatic tumors. Purohit et al. (47) found that in PDAC, CXCR2 is crucial for the migration of neutrophils from the spleen to the tumor. PC mice with CXCR2 gene knockout are more prone to LM than wild-type mice. Strøbech et al. (48) found that mice with the feline sarcoma oncogene (FES) knocked out have a decreased probability of neutrophil-dependent PDAC LM. Huo et al. (49) found that gap junction protein beta 3 (GJB3) can promote the conversion of cAMP from cancer cells to neutrophils, thereby promoting the polarization of neutrophils and ultimately inhibiting HMPC. Xu et al. (50) revealed that nuclear factor erythroid 2 (NFE2)-mediated neutrophil polarization promotes LM progression in PC. Han et al. (51) found that patients with higher levels of systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) may be more likely to develop early HMPC. In addition, NLR can also be used to assess the efficacy of combination chemotherapy in metastatic PC patients (52). These findings provide new targets and strategies for the treatment of PC (Figure 3).

Figure 3 Related pathways of neutrophils. FES and GJB3 activate neutrophils, which in turn activate CXCL and ultimately NETs. HMGB1 activates CXCL and thus NETs (43,46,49). CXCL, chemokine ligand; FES, feline sarcoma oncogene; GJB3, gap junction protein beta 3; HMGB1, high-mobility group box 1; NET, neutrophil extracellular trap.

The role of effector T cells and macrophages

Effector T lymphocytes are the main components of lymphocytes, which are functionally divided into cytotoxic T lymphocytes (CD8⁺ T cells) and helper T lymphocytes (CD4⁺ T cells). Yi et al. (53) discovered that activated invariant natural killer T cells can enhance the function of natural killer cells and T cells, suppress TAMs, and ultimately inhibit the LM of PC. Shankara Narayanan et al. (54) found that irreversible electroporation (IRE) can induce local tumor regression and a new antigen-specific immune response. Adding CD40Ab to IRE can improve dendritic cell activation and new antigen recognition, while generating a strong systemic anti-tumor T cell response, inhibiting the progression of LM in PC. Zhu et al. (55) identified that lysine acetyltransferase (KAT) 8-mediated acetylation of selenoprotein P (SEPP1) at lysine 247/249 regulates CD8⁺ T cell activity via low-density lipoprotein receptor-related protein 8 (LRP8), leading to the suppression of hepatic metastasis in PC. Bojmar et al. (56) found that a liver biopsy can be performed at the time of PC diagnosis to determine whether there is metastasis. NETs may form before LM, and CD3⁺ T cells are key anti-metastatic effector cells that can be detected to assist in determining metastatic status. Beckinger et al. (57) found that hepatic myofibroblasts may impair CD8⁺ T cells, exacerbating LM of PDAC. Astuti et al. (58) found that drug blockade of efferocytosis or macrophage-specific granulin gene deletion can inhibit macrophage transformation, improve CD8⁺ T cell function, and suppress LM of PDAC. Targeting macrophage efferocytosis may be an attractive new treatment strategy for patients with metastatic PDAC. Crissy Dudgeon et al. (59) found that the Netrin-1 feedforward mechanism first activates the secretion of retinoids through hepatic stellate cell activation, then activates the RAR/RXR/ELF3 signal transduction, ultimately promoting HMPC. Thomas et al. (60) found that in a PC mouse model, β-glucan activates Kupffer cells, inhibits cancer cell proliferation, and activates T cells, inhibiting LM of PDAC. Geng et al. (61) found that miR-124 promotes macrophage activation by directly targeting the Notch ligand Jagged 1. IL-6 from activated macrophages activates STAT3, which in turn suppresses the miR-124 gene, thereby promoting epithelial-mesenchymal transition (EMT) in cancer cells and exacerbating HMPC. Huang et al. (62) found that the CCR5 antagonist maraviroc inhibits LM of PC by inhibiting the cell cycle and inducing apoptosis. Other potential mechanisms caused by maraviroc (MVC), such as macrophage re-polarization, require further research. Ho et al. (63) found that the combination of anti-PD-1 and gemcitabine inhibits LM of PC by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages. Novizio et al. (64) found that ANXA1 in extracellular vesicles can promote macrophage polarization, ultimately exacerbating LM of PC. In summary, T cells and macrophages are essential in HMPC and are critical targets in immunotherapy strategies. Research advances have shown that specific T cell and macrophage subpopulations are closely associated with metastasis and prognosis of PC, providing new perspectives and strategies for future treatment. Mia et al. (65) demonstrated that the YAP/TAZ-MBD2-TGFβ1-pSMAD2 axis promotes macrophage polarization and induces fibroblast-to-myofibroblast transdifferentiation. Thus, interactions with fibroblasts and macrophages in PC warrant further investigation.

Metabolic pathways of HMPC

Metabolomics is the analysis of endogenous low molecular weight metabolites present in specific biological samples (such as tissues) or body fluids (such as blood) (66). Wang et al. (67) found that bile acids, glycine, and purine metabolites are associated with HMPC. Further exploration of their respective mechanisms is needed. Sarkar et al. (68) discovered that conjugated bile acids in cholestasis accelerate the LM of PC by activating the S1PR2 pathway. The creatine-phosphate-ATP system plays an important role in the invasive migration, chemotaxis, and LM of cancer cells. Cytoplasmic creatine kinase CKB can inhibit ECM-induced HMPC (69). Liu et al. (70) found that glutamine is a substrate for glycosylation and carbohydrate antigen 19-9 (CA19-9) biosynthesis through the hexosamine biosynthetic pathway in PC. The blockade of glutamine may be a potential therapeutic strategy for HMPC. Metabolic reprogramming is an important process for cancer cells to adapt to high energy demands and to replenish biosynthetic building blocks. Cancer cells exhibit abnormal metabolism, showing high glycolysis even under oxygen-rich conditions, a phenomenon known as aerobic glycolysis or the Warburg effect (71). Cancer shifts cellular metabolism to glycolysis under oxygen-rich conditions, and inhibiting glycolytic pathways is considered a new strategy for cancer treatment (72,73). Chao et al. (74) found that SLP-2 can promote the expression of GFPT2, promoting the movement of tumor cells and glucose uptake, ultimately exacerbating HMPC. Miyazaki et al. (75) found that gemcitabine can activate GFPT2, thereby activating the hexosamine biosynthetic pathway and exacerbating HMPC. Nimmakayala et al. (76) found that LM exhibits aerobic glycolysis and oxidative metabolism mediated by fatty acid β-oxidation (glycolytic oxidation). Li et al. (77) demonstrates that ITGA3 enhances glycolysis and promotes PC progression and metastasis by upregulating HIF1α and c-Myc expression through a collagen I-dependent autocrine mechanism. PDAC cell in vitro LM models show enrichment of MDR1+ and CPT1A+ populations. Additionally, compared to human primary PDAC tumors, a significant increase in the expression of MDR1/LDH-A in LM was observed. Arneson-Wissink et al. (78) found that PDAC inhibits lipid β-oxidation and suppresses ketone production in the liver, which is reversed in transgenic mouse models lacking IL-6/STAT3 signaling or through supplementation with a ketogenic diet. These findings inform therapeutic strategies for the mechanisms of PC liver metastases.

The role of the STAT family

The STAT family comprises seven members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, and is involved in multiple cellular processes (79,80). Hu et al. (81) discovered that the ALOX5 inhibitor zileuton can inhibit the JAK/STAT pathway, thereby suppressing tumor-associated M2 polarization and ultimately inhibiting HMPC. Marimuthu et al. (82) found that MUC16 can activate the JAK2/STAT1 pathway, thereby activating NRP2-related cell adhesion and ultimately exacerbating PDAC LM. Jiang et al. (83) found that inhibiting STAT1/V-set and immunoglobulin domain-containing 4 (VSIG4) can promote T cell recruitment and suppress PDAC LM. Chang et al. (42) discovered that PDAC cell-derived sEV-EZR induces the activation of fibroblasts through increased STAT3 signaling, with activated fibroblasts further promoting the proliferation, invasion, and LM of PDAC adenocarcinoma cells. Raymant et al. (84) found that leukemia inhibitory factor (LIF) secreted by cancer cells and granulin precursors from macrophages can activate the STAT3/myMAF pathway, thereby suppressing T cell function and exacerbating LM of PC. Thomas (85) found that IL-6 can activate the JAK-STAT3 pathway, activating serum amyloid A (SAA), which promotes the activation of hepatic stellate cells, thereby recruiting myeloid cells and increasing fibrotic deposition, ultimately exacerbating HMPC. Qiu et al. (86) discovered that alcohol can activate the IL-6/STAT3/LCN2 pathway, promoting immune evasion and exacerbating HMPC. Pozios et al. (87) found that raloxifene can inhibit HMPC by suppressing the ERβ and IL-6/gp130/STAT3 pathways, and further investigation is needed into the specific relationship between the ERβ and IL-6/gp130/STAT3 pathways. STAT protein plays a vital role in HMPC, and its aberrant activation is closely related to the tumor’s malignant behavior. Intervention strategies targeting STAT may provide new avenues for treating HMPC (Figure 4). Sun et al. (88) showed that FAPα⁺CD144⁺ CAFs activated the CD144/β-catenin/STAT3 pathway, enhancing angiogenic mimicry and paracrine signaling to aggravate hepatic metastasis of PC. Thus, CAFs-STAT pathway interactions warrant further investigation.

Figure 4 Related pathways of the STAT family. LIF, IL-6 and ALOX5 can activate STAT3, and STAT3 can activate LCN2 and M2, respectively. MUC16 triggers STAT1 activation, which subsequently upregulates the expression of NRP2 and VSIG4 (81,82,84,86). IL, interleukin; LIF, leukemia inhibitory factor; MUC16, mucin 16; NRP2, neuropilin-2; VSIG4, V-set and immunoglobulin domain-containing 4.

The role of YAP

YAP and PDZ-binding motif-containing transcriptional co-activator (TAZ) were first discovered in Drosophila in 1995. YAP has two main isoforms: YAP1, which contains one WW domain, and YAP2, which contains two WW domains (89). Zhang et al. (90) found that YAP shRNA can reduce the invasive migration of cells in vitro Transwell chamber experiments in human PC cell lines (Colo-357, Panc-1, BxPC-3). He et al. (91) discovered that the prostaglandin receptor prostaglandin E receptor 4 (EP4) inhibitor L001 can inhibit the EP4-YAP pathway, thereby inhibiting HMPC. Li et al. (92) found that YAP1 can activate the GTPase guanine nucleotide exchange factor epithelial cell transforming sequence (ECT2), exacerbating the LM of PDAC. Xiang et al. (93) found that phosphorylated proteins stimulated by vasodilators promote the activation of the β1-integrin-focal adhesion kinase (FAK)-YAP1/TAZ signaling pathway through the ECM, ultimately promoting HMPC. Chang et al. (42) also found that sEV-EZR induces the activation of fibroblasts through increased YAP-1 signaling, ultimately promoting the LM of PDAC cells. In summary, YAP plays a vital role in HMPC, and the regulation of its expression and activity may be a potential target for PC therapy. Inhibiting the activity of YAP may help control the invasion and metastasis of PC (Figure 5). Mia et al. (65) demonstrated that the YAP axis promotes macrophage polarization and induces fibroblast-to-myofibroblast transdifferentiation. Thus, YAP’s interactions with fibroblasts and macrophages in PC warrant further investigation.

Figure 5 YAP related pathway. Prostaglandin EP4, sEV-EZR, and β1-integrin-FAK can all activate YAP, and YAP can activate ECT2 (83,89). ECT2, epithelial cell transforming sequence; EP4, E receptor 4; FAK, focal adhesion kinase; sEV-EZR, small extracellular vesicle ezrin; YAP, Yes-associated protein.

The role of protein kinase B (AKT)

AKT, also known as PKB, is a crucial serine/threonine kinase involved in various cellular activities such as cell proliferation, metabolism, and migration. The dysregulation of AKT signaling is associated with malignant tumors (94). Suzuki et al. (95) found that in patients with HMPC, those with high levels of GDF-15 exhibit increased expression of AKT and c-Jun N-terminal kinase (JNK), suggesting that the AKT/JNK pathway may play a role in HMPC and warrants further investigation. Zhao et al. (96) discovered that blocking programmed death-ligand 1 (PD-L1) might inhibit the growth and metastasis of PC by promoting the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Cao et al. (97) found that hypoxia can upregulate the expression of miR-4465 and miR-616-3p in exosomes derived from PSCs, thereby inhibiting the PTEN/AKT pathway and promoting HMPC. Wan et al. (98) found that microRNA-382 can suppress the PI3K/Akt pathway by inhibiting Annexin A3 (Anxa3), ultimately inhibiting HMPC. Li et al. (99) discovered that tripartite motif-containing protein 59 (TRIM59) can activate the PI3K/AKT/mTOR pathway, promoting glycolysis and exacerbating HMPC. Zheng et al. (100) found that the IGF-1/PI3K/Akt/mTOR pathway increases the phosphorylation of HDAC3 at the S424 site, inducing the deacetylation of K394, thereby stimulating ENO2 activity and ultimately promoting HMPC. Therefore, IGF-1R inhibitors, such as linsitinib, may serve as effective drugs for patients with HMPC. Shi et al. (101) found that the complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts can activate the IGF-1/PI3K and mitogen-activated protein kinase (MAPK) pathways, ultimately promoting HMPC. Zhang et al. (102) found that laminin subunit beta-3 (LAMB3) can activate the PI3K/AKT/mTOR pathway, exacerbating the LM of PDAC. This study may provide potential targets and new therapeutic strategies for controlling the invasion and metastasis of PDAC using these PI3K signal transduction pathway inhibitors in the future. Zhang et al. (103) found that MicroRNA-23b-3p can activate the JAK/PI3K and Akt/NF-κB pathways, promoting HMPC. Zhang et al. (104) discovered that ZNF263 and ZNF31 together promote the ubiquitination-mediated degradation of PTEN by inactivating RNF126. The downregulation of PTEN activates the AKT/Cyclin D1 and AKT/GSK-3β/β-catenin signaling pathways, promoting drug resistance and EMT in PC, ultimately promoting the LM of PDAC. Yoshida et al. (105) found that metformin can inhibit the SMAD3 and AKT/mTOR pathways mediated by transforming growth factor-1 (TGF-1), thereby inhibiting HMPC. Wang et al. (106) found that LINC00941 can bind to ANXA2 and inhibit the NEDD4L-mediated degradation of ANXA2, thereby activating the FAK/AKT pathway and ultimately promoting HMPC. The role of the AKT signaling pathway in HMPC is multifaceted. It promotes tumor cell migration and invasion, regulates macrophage polarization, influences the TME, and serves as a potential therapeutic target (Figure 6). Xia et al. (107) demonstrated that CD53 inhibition suppresses the AKT pathway, thereby reducing NETs formation and attenuating acute pancreatitis progression. Pancreatitis is an important cause of PC. Consequently, AKT-NETs interactions merit further investigation.

Figure 6 Related pathways of the AKT family. LAMB3, Anxa3, TRIM59 and IGF-1 activate PI3K/AKT/mTOR pathways, respectively (99,101,102). AKT, protein kinase B; Anxa3, annexin A3; IGF-1, insulin-like growth factor-1; LAMB3, laminin subunit beta 3; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3-kinase; TRIM59, tripartite motif-containing protein 59.

The role of extracellular signal-regulated kinase (ERK)

ERKs, also known as MAPKs, are integral to various biochemical signals and influence processes such as cell proliferation, differentiation, transcription, and development (108). He et al. (109) discovered that inhibiting the PCSK6-Raf-MEK1/2-ERK1/2 pathway can suppress HMPC. Yan et al. (110) found that thrombopoietin can activate CD110, subsequently activating ERK-MYC, which exacerbates LM. Yan et al. (111) found that the combined use of an ERK inhibitor and the autophagy inhibitor chloroquine can accelerate the senescence of cancer-associated PSCs, ultimately inhibiting LM in a mouse model of PC. This suggests that a combined therapy targeting ERK1/2 and autophagy could be a potential treatment for PC. Hu et al. (112) found that activating the miR-361-3p/dual specificity phosphatase 2 (DUSP2)/ERK axis can intensify EMT, ultimately promoting HMPC. Jiao et al. (113) discovered that the paired protein kinases PRKCI-RIPK2 promote the growth and metastasis of PC by activating the NF-κB/JNK/ERK pathway. The detailed interaction pattern between protein kinase RIPK2 and PKC iota is not yet clear, and this study mainly focuses on the expression levels of protein kinases, with future research needed to further explore the mutual influence of enzymatic activities between RIPK2 and PRKCI. The ERK signaling pathway plays a crucial role in LM in PC. It affects the progression and metastasis of PC by promoting tumor cell migration, invasion, and proliferation. These studies provide a basis for developing therapeutic HMPC strategies (Figure 7). Zhu et al. (114) demonstrated that inhibiting the E3 ubiquitin ligase Cbl-b activates the ERK pathway, enhancing T-cell activation. This study clarifies the ERK-T-cell relationship and suggests the therapeutic potential in PC.

Figure 7 ERK related pathway. MAPK, DUSP2 and JNK activated by NF-κB can activate ERK, and ERK can activate MYC (108,112). DUSP2, dual specificity phosphatase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B.

EMT intervention in HMPC

EMT is a classic cellular plasticity process induced by various intrinsic and extrinsic triggers (115). Yang et al. (116) found that p21-activated kinase 2 (PAK2) activates TGF-β to promote angiogenesis in cancer cells, facilitating EMT. This reduces the differentiation level of cancer cells, thereby enhancing the malignancy of cancer cells. PAK2 is a key gene in regulating HMPC. Weng et al. (117) discovered that TMC7 can promote EMT, promoting HMPC, and can be considered a potential therapeutic target in the future. Yang et al. (118) found that ERO1L can promote EMT, ultimately promoting the LM of PDAC. Early growth response 1 (EGR 1) can activate the P300/SNAI2 pathway, exacerbating EMT and promoting HMPC. Therefore, blocking the EGR1-SNAI2 pathway may be a new strategy for the treatment of PC. Ji et al. (119) found that hypoxia/glycogen phosphorylase L/glycolysis-induced HMPC promotes the LM of PDAC. Combined targeting of glucose metabolism may provide a new therapeutic strategy for PDAC, which is highly metastatic and resistant to existing treatment methods. A limitation of the study is that the role of nuclear PYGL in PDAC, especially in EMT, cannot be excluded. Zhang et al. (120) found that MACC1, by binding to the EMT regulator SNAI1, promotes the metastasis of PC. Whether MACC1 promotes the transcriptional activity of SNAI1 by regulating its acetylation remains to be further studied. Wong et al. (121) found that the activation of the circRTN4-miR-497-5p-HOTTIP and circRTN4-RAB11FIP1t pathways can promote EMT, ultimately exacerbating the LM of PDAC. Borrelli et al. (122) found that agrin B2 is a key host-derived regulator of liver colonization. The authors found that agrin B2 interacts with class IV signal proteins on tumor cells, thereby promoting the upregulation of KLF4, promoting epithelialization, and exacerbating LM. Epithelialization is a necessary condition for metastatic foci to adapt to the new tissue environment. Blocking the agrin B2 signal protein axis can eliminate metastatic colonization of the liver and is therefore a therapeutic strategy for preventing LM. Zu et al. (123) discovered that Smad2 and TGF-β-induced factor homeobox 2 (TGIF2) co-regulate the sex determining region Y-box 2 (SOX2) promoter, which promotes EMT through the transactivation of Slug and EGFR. EMT plays a crucial role in LM of PC, which not only promotes the migration and invasion of cancer cells but also relates to the interaction between tumor stem cell properties and the liver microenvironment, which together promote LM of PC.

Conclusions

HMPC remains a major challenge in PC treatment, but recent advances in therapeutic strategies and molecular mechanism research offer hope. Immunotherapy, by enhancing the patient’s immune response, shows potential as an effective treatment. Understanding the TME and key molecular mechanisms, such as EMT and metabolic reprogramming, provides new targets for therapeutic intervention. Future research must focus on four key mechanistic axes: first, elucidating CAFs-STAT3 signaling in PC hepatic metastasis; second, defining YAP-mediated macrophage polarization dynamics; third, characterizing AKT-regulated NETosis pathways; and fourth, exploring ERK-T-cell crosstalk for immunotherapeutic applications. These interconnected mechanisms represent critical therapeutic targets within the pancreatic TME. Research on PC with comorbid metabolic liver disease or aging-related mechanisms remains notably scarce in recent years. Both metabolic liver disorders and senescence may critically reshape the immune microenvironment of hepatic metastases. Continued research into these mechanisms will be crucial for improving the prognosis of PC patients with LM.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-38/prf

Funding: The study was funded by the National Natural Science Foundation of China (No. 52373294).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-38/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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