In addition to the existing list of oncogenes/proto-oncogenes, recent reports on the identification of cancer-specific genes and their potential in cancer pathogenesis lead to the identification of new molecular targets [
1‐
4,
11]. For a long time, MAGEA3 has been on light for hope as cancer immunotherapeutic [
63,
64]; however, recent findings emphasizes on its functional role in the pathogenesis of different malignancies [
16,
20,
22,
27]. In the current study, we report the cancer-promoting/favoring role of MAGEA3 in PCA. Our findings suggest that the PCCs expressing MAGEA3 are dependent on it to survive and thrive both in growth factor enriched and growth factor depleted condition (Figs.
1 and
2). However the cells, those are negative for MAGEA3 expression, don’t depend on it when desired growth factors are available (Fig.
1), but in growth factor limiting condition, ectopic expression of MAGEA3 is able to help the cancer cells to survive (Fig.
2 and Additional file
4: Figure S3). The cell lines used in this study have different oncogenic KRAS and P53 status (BxPC3 has WT-KRAS and Mut-TP53; AsPC1, MiaPca2 and PANC1 have Mut-KRAS and Mut-TP53) [
65]; however, in the current study, we have not experimentally explored the correlation between KRAS and P53 status with MAGEA3 function. Hence, future studies in these aspects might elucidate the influence of common genetic aberrations on MAGEA3 function in pancreatic cancer cells.
In cancer cells, impaired autophagy was reported to be an important protumorigenic mechanism that supports the metabolic switching of cancer cells and favors Warburg’s effect [
15,
16,
20,
56,
57]. Though early autophagy inhibition during GF-deprivation may provide pro-survival gain; prolonged autophagy inhibition can be lethal during continuous energy stress [
56,
57]. Our study demonstrates that MAGEA3 reduces the autophagy level in PCCs, which agrees with earlier reports [
15‐
17,
20]. Importantly, the reduced autophagy level during growth factor limitation provided a pro-survival advantage to the MAGEA3 over-expressing PCCs. Cancer cells have been reported to produce and use important chemokines in survival signalling pathways, which can be a potential factor responsible for the survival of cancer cells in prolonged GF-deprivation [
58,
59,
66,
67]. Upon ectopic expression of MAGEA3, CCL2 and survivin were found to be up-regulated; conversely, upon MAGEA3 depletion both CCL2 and survivin level was reduced. A previous report had already shown the integrated role of CCL2 and survivin in reducing autophagy and providing survival advantage [
60,
61]. Acquisition of intrinsic properties to overcome various metabolic stresses including GF-deprivation is one of the essential hallmarks of cancer cells [
68,
69]. In cell line based in vivo tumor models, although the cells that are used to generate tumors are already transformed, but in absence of proper angiogenesis (during the initial establishment of tumors and at the core region of the fast-growing tumors) many cancer cells encounter sustained GF-deprivation and succumb to death. In our study, the presence of more number of cancer cells in MAGEA3 overexpressing tumors might be due to better survival and/or proliferation of cancer cells in tumor tissues (Fig.
6d and e). Our in vitro studies have provided convincing evidence that shows the role of MAGEA3-mediated autophagy inhibition as a potential mechanism through which MAGEA3 directly promotes survival of GF-deprived PCCs in vitro. However, in the in vivo context, in addition to this direct effect, MAGEA3 might have also indirectly affected the overall tumor growth by modulating different stromal events like angiogenesis. CCL2 is known to promote angiogenesis in different cancers [
70‐
72]; hence, MAGEA3-mediated CCL2 overexpression in pancreatic cancer cells (Fig.
4c-e and g) might have also indirectly contributed to the overall tumor growth in vivo
, which warrants further investigation. We also found that MAGEA3 is able to upregulate survivin in mouse primary pancreatic epithelial cells (Fig.
4i), which indicates the possible oncogenic role of MAGEA3 and needs further investigation. Our study involves the molecule MAGEA3 which is highly similar to MAGEA6. Although MAGEA3 and MAGEA6 are two different gene products, but due to their high similarity at protein level (> 90%), in different literatures both the genes have been reported together (MAGEA3/6) [
16]. In the current study, we have used MAGEA3 coding sequence for its overexpression; however, the siRNA used by us might act on both the genes. Hence, we believe that the findings of the current study might also be true for MAGEA6 function in PCA.
Together, our study confirms the survival advantage provided by MAGEA3 during the hostile condition to PCCs. Moreover, the results of this study provide a rationale to target MAGEA3 and/or associated molecules like CCL2 for personalized PCA therapy. Further, we targeted MAGEA3 in PCCs and observed enhanced cytotoxic effect of various existing molecules upon MAGEA3 depletion but the cytotoxic effect is reduced when MAGEA3 is overexpressed in PCCs. Thus, it cautious the strategy to overexpress molecules like MAGEA3 in pancreatic cancer cells, which will make them more immunogenic like in other cancers [
73‐
76] but may have a serious negative consequence. In the future, along with existing chemotherapy, MAGEA3-targeted therapy can be explored for a better therapeutic approach against PCA.