Metastasis-associated in colon cancer 1 in pancreatic ductal adenocarcinoma: Emerging evidence, unresolved questions, and future perspectives

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a poor prognosis. Metastasis-associated in colon cancer 1 (MACC1) has been implicated in the progression of multiple malignancies; however, its role in PDAC has not been fully clarified. This review summarizes the relevant evidence of the biological functions and molecular mechanisms of MACC1 in PDAC. Its mechanism of action may involve MET/extracellular signal-regulated kinase/protein kinase B, protein kinase B/mammalian target of rapamycin, epithelial-mesenchymal transition, and p53/Notch-related signaling pathways. In addition, MACC1 is regulated by upstream non-coding RNAs. However, existing studies remain limited by inadequate mechanistic validation and insufficient consideration of molecular heterogeneity. Future studies should integrate phenotype-oriented analyses, mechanistic validation, and genotype-stratified approaches to comprehensively clarify the functional role of MACC1 in PDAC.

Key Words: Pancreatic cancer; Metastasis-associated in colon cancer 1; P53; Notch; Non-coding RNA

Core Tip: Current evidence indicates that metastasis-associated in colon cancer 1 is not just a simple prognostic marker of pancreatic ductal adenocarcinoma but is also involved in tumor invasion, metastasis, chemotherapy resistance, and multiple signaling pathways, and is regulated by upstream non-coding RNAs. However, its key functions, mechanistic hierarchy, and context-dependent roles remain unclear. This review summarizes the existing evidence, unresolved questions, and future research directions, aiming to provide a reference for further elucidating the core regulatory mechanisms of metastasis-associated in colon cancer 1 in pancreatic ductal adenocarcinoma.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant tumors of the digestive system[1]. Its overall prognosis remains extremely poor, with an overall 5-year survival rate of about 10%. The main factors leading to this poor outcome include its clinically silent early course and the lack of effective screening methods[2,3]. Therefore, most patients are already in distant metastasis at the time of diagnosis, thus missing the opportunity for radical surgery. In addition, significant tumor heterogeneity, complex tumor microenvironment, and resistance to traditional chemotherapy and radiotherapy together constitute the core obstacles in the treatment of PDAC[4]. Although liquid biopsy[5], organoid models[6], and targeted therapies have made some progress in the diagnosis and treatment of cancer, existing technologies still face major challenges in the early detection, reliable stratification, and achievement of durable therapeutic benefits in pancreatic cancer[7]. Therefore, there is an urgent need to develop reliable early detection biomarkers and targets with therapeutic value[8].

Metastasis-associated in colon cancer 1 (MACC1) was originally identified in colorectal cancer as a metastasis-driving gene[9]. Recent studies have shown that it is also involved in tumor development and metastasis in a variety of cancers[10-12]. In addition, abnormal MACC1 expression has been observed in tumor tissue and peripheral blood, suggesting that MACC1 may play a dual role as both a biomarker and a functional driver[13]. MACC1 can enhance the hepatocyte growth factor/mesenchymal-epithelial transition factor (c-MET) signaling axis, thus activating downstream pathways such as phosphatidylinositol 3-kinase-protein kinase B (AKT) and RAS-mitogen-activated protein kinases, and promoting the proliferation and migration of tumor cells[14]. In addition, MACC1 is involved in receptor endocytosis[15], maintenance of tumor stemness[16], anti-apoptotic activity[17], inflammatory responses[18], and metabolic reprogramming[19]. It also interacts with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), thus playing a more diverse regulatory role in tumor progression[20,21]. However, the core biological function of MACC1 in PDAC and whether its regulatory role is context-dependent still need to be systematically clarified.

Based on this background, this review critically summarizes existing research on MACC1 in PDAC, analyzes the main limitations of current research, and discusses future research directions. We aim to provide a clearer conceptual framework for understanding the functional role of MACC1 in the progression of PDAC and its potential translational value.

CURRENT EVIDENCE FOR MACC1 IN PANCREATIC CANCER

Although research on MACC1 in PDAC is still in its early stages, existing evidence has begun to reveal its role from upstream regulation to malignant phenotypes. This evidence can be broadly divided into two aspects: The diverse effects of MACC1 on downstream malignant phenotypes and its regulation by upstream non-coding RNA (ncRNA) networks (Figure 1 and Table 1).

Figure 1 Schematic overview of the regulatory network of metastasis-associated in colon cancer 1 (MACC1) in pancreatic ductal adenocarcinoma (PDAC). Upstream regulators include the circPDE8A/miR-338 and interferon-gamma/MACC1-AS1 axes. MACC1 participates in key PDAC-associated signaling pathways, including MET/protein kinase B, extracellular signal-regulated kinase, and p53/Notch-related signaling. Downstream effects comprise invasive growth, metastasis, and snail family transcriptional repressor 1-mediated epithelial-mesenchymal transition via FN1 upregulation and CDH1 suppression, ultimately promoting migration, invasion, liver metastasis, chemoresistance, and proliferation. AKT: Protein kinase B; EMT: Epithelial-mesenchymal transition; ERK: Extracellular signal-regulated kinase; FN1: Fibronectin 1; IFN-γ: Interferon-gamma; MACC1: Metastasis-associated in colon cancer 1; PDAC: Pancreatic ductal adenocarcinoma; SNAI1: Snail family transcriptional repressor 1.

Table 1 Main evidence supporting the role of metastasis-associated in colon cancer 1 in pancreatic cancer.

Mechanistic axis	Major phenotypes	Main implication	Ref.
MACC1-RAS/ERK	Proliferation, migration, gemcitabine response, and associations with metastasis and advanced-stage disease	Provides early clinical and functional evidence for the role of MACC1 in PDAC	Wang et al[22]
MACC1-SNAI1-FN1/CDH1	Migration, invasion, EMT, and liver metastasis	Supports a pro-metastatic driver role of MACC1	Zhang et al[23]
p53/Notch-related signaling	Proliferation, migration, invasion, and apoptosis	Suggests broader roles for MACC1 in malignant progression	Cong et al[27]
circPDE8A/miR-338/MACC1/MET/ERK-AKT	Invasive growth and exosome-mediated signal amplification	Suggests that MACC1 participates in upstream ncRNA-mediated regulatory networks	Li et al[30]
IFN-γ/MACC1-AS1/MACC1/AKT-mTOR	Malignant phenotypes and survival signaling	Suggests upstream lncRNA-mediated regulation of MACC1	Shi et al[33]

AKT: Protein kinase B; EMT: Epithelial-mesenchymal transition; ERK: Extracellular signal-regulated kinase; FN1: Fibronectin 1; IFN-γ: Interferon-gamma; lncRNA: Long non-coding RNA; MACC1: Metastasis-associated in colon cancer 1; mTOR: Mammalian target of rapamycin; ncRNA: Non-coding RNA; SNAI1: Snail family transcriptional repressor 1; PDAC: Pancreatic ductal adenocarcinoma.

In terms of clinical relevance and phenotypic driving effects, MACC1 exhibits clear pro-malignant characteristics. Wang et al[22] first reported, through serological analysis, that high MACC1 expression was significantly associated with lymph node metastasis, distant metastasis, and advanced TNM stage. They further demonstrated that MACC1 suppression increased the sensitivity of pancreatic cancer cells to gemcitabine. These findings support the potential of MACC1 as a liquid biopsy biomarker. More importantly, they provide the first evidence that MACC1 mediates intrinsic resistance to conventional chemotherapy, particularly to gemcitabine.

Subsequently, Zhang et al[23] used TCGA data, tissue microarrays, and both in vitro and in vivo models to further demonstrate that MACC1 promotes pancreatic cancer cell migration, invasion, and liver metastasis. MACC1 enhances snail family transcriptional repressor 1 (SNAI1) transcriptional activity by directly interacting with it, thereby driving EMT. Activation of EMT typically promotes cancer stemness[24,25]. Notably, as MACC1 also maintains stemness in other gastrointestinal tumors[26], the acquisition of stemness during EMT may represent a central mechanism by which MACC1 promotes the progression and metastasis of PDAC. More recently, Cong et al[27] further expanded the function of MACC1. They found that MACC1 can regulate the proliferation and apoptosis of pancreatic cancer cells through the p53 and Notch signaling pathways. In PDAC, p53 mutations can promote tumor development and drug resistance, whereas Notch signaling promotes tumor metastasis and the maintenance of stemness[28,29]. Therefore, the function of MACC1 in PDAC is not limited to promoting metastasis, but may also exert broader regulatory effects on processes such as cell survival. In summary, these studies indicate that MACC1 is more than just a potential prognostic marker and may serve as a key regulatory factor in PDAC development and progression.

In terms of upstream regulation, MACC1 does not act as an isolated oncogenic driver but rather operates within a highly dynamic ncRNA regulatory network. Li et al[30] demonstrated in liver metastasis-derived PDAC cells that circPDE8A can function as a competing endogenous RNA sponge for miR-338, thus relieving its inhibitory effect on MACC1 and upregulating downstream MET/extracellular signal-regulated kinase (ERK)/AKT. Tumor-derived exosomes partially contribute to this oncogenic signaling amplification, which depends on circPDE8A[31]. This implies that aberrant MACC1 activation is not confined to individual cancer cells. Exosomes can transmit signals to promote invasion and metastasis between different tumor subgroups, and even to distant organs such as the liver, thus reshaping the metastatic microenvironment[32]. Similarly, the lncRNA MACC1-AS1 has been implicated in the progression of pancreatic cancer as a key regulatory factor to maintain transcription[33]. In terms of mechanism, antisense lncRNAs can form RNA-RNA duplexes with their corresponding mRNAs, protecting them from degradation and improving transcript stability[34,35]. The synergistic expression of MACC1-AS1 and MACC1 may constitute a stress-adaptive stability mechanism. In summary, MACC1 may serve not only as a potential prognostic marker in PDAC but also as a molecular hub linking ncRNA regulation, oncogenic signaling, and malignant progression.

UNRESOLVED QUESTIONS REGARDING THE ROLE OF MACC1 IN PDAC

Although MACC1 plays an important role in PDAC progression, its dominant function, mechanistic hierarchy, and pathway dependence remain unclear.

First, the dynamic selection of downstream signaling pathways remains unclear. In other tumor types, the classical pro-metastatic function of MACC1 usually depends on the hepatocyte growth factor/c-MET axis. In PDAC, however, Li et al[30] suggested that MACC1 can be incorporated into the circPDE8A-miR-338-MACC1/MET-ERK cascade and may further activate ERK/AKT signaling pathways. In contrast, Zhang et al[23] found that MACC1-driven metastasis may not depend on the classical MET pathway. Instead, it interacts with the EMT regulator SNAI1 to enhance its transcriptional activity, thereby upregulating fibronectin 1[36], suppressing CDH1[37], and promoting liver metastasis. The c-MET axis is generally regarded as an upstream inducer of EMT, whereas SNAI1[38] is a core transcription factor that promotes phenotypic remodeling[39-41]. Therefore, the coexistence of these MET-dependent and MET-independent modes is not necessarily contradictory. Rather, it may suggest that MACC1 engages different downstream programs under different contexts. Whether these differences are primarily determined by the intrinsic molecular background of tumor cells or by differences in experimental input modes, such as exosome-mediated paracrine stimulation vs direct gene overexpression, remains uncertain.

Second, the mechanistic relationship between MACC1 and p53/Notch-related signaling remains insufficiently defined. Cong et al[27] reported that MACC1 regulates the downstream phenotype of PDAC through the p53/Notch-related signaling pathway, thereby expanding the mechanism framework of MACC1 in PDAC. However, the direct interaction between MACC1 and the p53/Notch signaling pathway was not further clarified in this study, leaving the core functional role of MACC1 in PDAC unclear. With regard to Notch signaling, its relationship with EMT[42], cellular plasticity, and maintenance of tumor stemness is already well established, making the biological plausibility of a MACC1-Notch axis in phenotypic remodeling relatively strong[43]. However, the p53 pathway is affected by the TP53 genotype. TP53 mutations such as R175H and R273H will not only lose their anticancer function but also may confer gain-of-function phenotypes[44-46]. As the specific TP53 mutation status was not specified in this study, it remains unclear whether MACC1 synergizes with mutant p53 to further promote cancer-related processes such as invasion, stemness, or metabolic adaptation.

Third, the regulation of MACC1 by upstream ncRNAs remains incompletely understood. MACC1 is not an independent oncogenic gene in PDAC, but may be part of an upstream regulatory network composed of molecules such as circular RNA[47], miRNA[48], and lncRNA[49]. Li et al[30] showed that tumor-derived exosomal circPDE8A can relieve miR-338-mediated repression of MACC1 and further activate the MET/ERK/AKT axis to drive invasive tumor growth. This suggests that ncRNAs may amplify malignant phenotypes by upregulating MACC1 and mobilizing its downstream signaling output. Shi et al[33] further reported that interferon-γ can modulate AKT/mammalian target of rapamycin signaling via the MACC1-AS1/MACC1 axis, suggesting that MACC1-AS1 may stabilize MACC1 and drive signaling toward cellular survival and metabolic adaptation. In addition, the reported role of MACC1-AS1 in gemcitabine resistance and ferroptosis suppression suggests that ncRNAs may also regulate treatment response[50].

However, several key questions remain unresolved. Do these ncRNAs act merely by modulating MACC1 expression levels, or do they also influence the specific downstream programs preferentially governed by MACC1, such as invasion, EMT, cell survival, or drug resistance? In addition, whether MACC1 is an essential component of ncRNA-mediated axes or a context-dependent regulatory hub remains unclear.

FUTURE RESEARCH DIRECTIONS FOR CLARIFYING MACC1 FUNCTION IN PDAC

Based on the unresolved questions and limitations in current MACC1 research in PDAC, several points should be addressed in future studies.

First, the primary phenotypic role of MACC1 should be systematically evaluated in unified models. However, current phenotypic studies of MACC1 in PDAC have been conducted in different models, making it difficult to determine which biological function of MACC1 is most critical for tumor progression. Future studies should systematically evaluate the effects of MACC1 on these different phenotypes. These evaluations must be conducted using the same cell lines, organoid systems, and in vivo models to enable direct comparisons across phenotypes. In addition, they should incorporate functional assays such as gene knockout, overexpression, and rescue experiments to establish causal relationships and define the relative contribution of MACC1 to each biological process.

Second, the position of MACC1 within the PDAC mechanistic network should be defined more precisely. MACC1 may be involved in multiple signaling pathways in PDAC. However, the specific hierarchy and key role of MACC1 in these signaling pathways remain unclear. Future research should first use a unified experimental model and combine time-course sampling[51], hierarchical perturbation approaches[52], and functional rescue strategies to clarify the functional hierarchy of MACC1 in the PDAC signaling network. In addition, multi-omics analysis[53], such as transcriptomics and proteomics, can further determine the core regulatory role of MACC1 in PDAC. Single-cell RNA sequencing[54] and protein interaction network analysis will further help elucidate the role of MACC1 across different cell types, thereby clarifying its regulatory role in tumor progression. Therefore, future research should combine the above strategies to fully reveal the functional hierarchy and principal oncogenic pathways of MACC1 in PDAC progression through systematic verification.

Third, mechanistic studies of MACC1 should clarify the TP53 genotype. Given that p53 mutations are very common in PDAC, distinct p53 states can lead to different transcription and phenotypic outcomes. Therefore, when investigating the relationship between MACC1 and p53-related signaling, it is essential to identify the specific p53 genotypes involved to determine whether the function of MACC1 in PDAC is context-dependent. In addition, transcriptomic analysis[55], chromatin occupancy profiling[56], and protein interaction studies could be used to examine whether MACC1 has direct or indirect functional links to mutant p53. Incorporating TP53 status into the mechanistic framework will be essential for understanding the context-dependent functions of MACC1 and for advancing the p53/Notch-related model proposed by Cong et al[27] from a suggestive association to a clearer mechanistic explanation.

Finally, future research on the regulation of MACC1 by ncRNA should identify the specific regulatory mechanisms involved. Current studies largely describe the regulatory pathways of ncRNAs in MACC1 regulation, and the specific mechanism of action has not been sufficiently explored. Existing evidence shows that circular RNA, miRNA, and lncRNA may regulate MACC1 at the upstream level; however, it remains unclear whether they simply alter the expression of MACC1 or further affect the downstream processes mediated by MACC1, such as invasion, EMT, survival, or drug resistance. In addition, future research on ncRNA regulation of MACC1 should not be limited to the classical competing endogenous RNA regulation framework, but should explore whether ncRNAs participate in the formation of MACC1-related molecular complexes, thus affecting the organization and functional output of intracellular signaling. MACC1 contains multiple potential protein-interaction domains and may facilitate multivalent interactions[57]. Whether it interacts with specific ncRNAs, such as MACC1-AS1, and thereby forms biomolecular condensates to promote cancer progression remains to be investigated[58,59]. If such a hypothesis proves valid, MACC1 would no longer be viewed simply as a regulated effector but also as an active participant in the spatial organization of local malignant signaling networks. To address this, future studies could further incorporate dependency testing, node elimination, and rescue strategies into the investigation of the circPDE8A/miR-338/MACC1/MET axis and the MACC1-AS1/MACC1 axis[60].

For example, MACC1 could be knocked out or re-expressed in the setting of specific ncRNA perturbations to determine whether the associated phenotypes are attenuated. By modulating upstream ncRNAs in the context of MACC1 overexpression or inhibition, we can determine whether these ncRNAs primarily function as expression regulators or play a more critical role in facilitating its oncogenic functions. In summary, a comprehensive understanding of the mechanisms and clinical significance of MACC1 in PDAC will require the integration of standardized experimental models, genotypic stratification, and more systematic validation.

CONCLUSION

Currently, research on MACC1 in PDAC remains limited. However, existing evidence suggests that MACC1 is not only a prognostic marker but also an active driver of various malignant phenotypes. MACC1 has been implicated in signaling pathways such as MET/ERK/AKT, AKT/mammalian target of rapamycin, SNAI1-EMT, and p53/Notch signaling, suggesting that it may be a key molecular hub in PDAC, regulating multiple downstream pathways. Nevertheless, it remains unclear to what extent MACC1 is regulated by upstream ncRNAs, what its core functions are, and which downstream pathways are most critical for its oncogenic activity. Future research should focus on systematic phenotype analysis, pathway verification, and genotype-based stratification in a unified experimental system to further clarify the functional and mechanistic hierarchy of MACC1. These studies will help determine whether MACC1 can be developed not only as a candidate biomarker but also as a therapeutically relevant target in PDAC.

ACKNOWLEDGEMENTS

We thank the reviewers for their valuable comments that helped improve the manuscript.