Amyloid precursor protein (APP) and its family members amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) are type 1 transmembrane glycoproteins that are highly conserved across species. The transcriptional regulation of APP and APLP2 is similar but not identical, and the cleavage of both proteins is regulated by phosphorylation. APP has been implicated in Alzheimer's disease causation, and in addition to its importance in neurology, APP is deregulated in cancer cells. APLP2 is likewise overexpressed in cancer cells, and APLP2 and APP are linked to increased tumor cell proliferation, migration, and invasion. In this present review, we discuss the unfolding account of these APP family members’ roles in cancer progression and metastasis.

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Beta 2-microglobulin (β 2 m) is a component of the major histocompatibility complex (MHC) class I molecule, which presents tumor antigens to T lymphocytes to trigger cancer cell destruction. Notably, β 2 m has been reported as persistently expressed, rather than down regulated, in some tumor types. For renal cell and oral squamous cell carcinomas, β 2 m expression has been linked to increased migratory capabilities. The migratory ability of pancreatic cancer cells contributes to their metastatic tendencies and lethal nature. Therefore, in this study, we examined the impact of β 2 m on pancreatic cancer cell migration. We found that β 2 m protein is amply expressed in several human pancreatic cancer cell lines (S2-013, PANC-1, and MIA PaCa-2). Reducing β 2 m expression by short interfering RNA (siRNA) transfection significantly slowed the migration of the PANC-1 and S2-013 cancer cell lines, but increased the migration of the MIA PaCa-2 cell line. The amyloid precursor-like protein 2 (APLP2) has been documented as contributing to pancreatic cancer cell migration, invasiveness, and metastasis. We have previously shown that β 2 m/HLA class I/peptide complexes associate with APLP2 in S2-013 cells, and in this study we also detected their association in PANC-1 cells but not MIA PaCa-2 cells. In addition, siRNA down regulation of β 2 m expression diminished the expression of APLP2 in S2-013 and PANC-1 but heightened the level of APLP2 in MIA PaCa-2 cells, consistent with our migration data and co-immunoprecipitation data. Thus, our findings indicate that β 2 m regulates pancreatic cancer cell migration, and furthermore suggest that APLP2 is an intermediary in this process.

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

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The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic cancer. In this study, we demonstrated that M344, an HDAC inhibitor, is efficacious against pancreatic cancer in vitro and in vivo, alone or with gemcitabine. By 24 hours post-treatment, M344 augments the population of pancreatic cancer cells in G1, and at a later time point (48 hours) it increases apoptosis. M344 inhibits histone H3 deacetylation and slows pancreatic cancer cell proliferation better than vorinostat, and it does not decrease the viability of a non-malignant cell line more than vorinostat. M344 also elevates pancreatic cancer cell major histocompatibility complex (MHC) class I molecule expression, potentially increasing the susceptibility of pancreatic cancer cells to T cell lysis. Taken together, our findings support further investigation of M344 as a pancreatic cancer treatment.

Beta 2-microglublin (β2m) is a 12-kilodalton protein that serves as the non-covalently bound light chain in complex with the major histocompability complex (MHC) class I heavy chain. The human MHC class I heavy chain is known as human leukocyte antigen (HLA), which exists in three isotypes (HLA-A, -B, and -C). Much of the known function of β2m is in regards to its role in stabilizing the HLA class I heavy chain and thereby helping to present endogenous antigenic peptides to cytotoxic T cells. Notably, β2m has recently been found to be elevated in expression in a variety of cancers, including renal cell carcinoma, oral squamous cell carcinoma, prostate cancer, lung cancer, breast cancer, and multiple lymphocytic malignancies. In most of these cancers, β2m is correlated with more advanced disease and poorer prognosis. It has also been shown that in some cancer models, such as a renal cell carcinoma and an oral squamous cell carcinoma model, β2m can affect the proliferation and migration of these tumor cells. The levels and effects of β2m in pancreatic cancer, however, have not been reported thus far. Recent results from our laboratory have revealed high expression of β2m in nearly all members of a panel of pancreatic cancer cell lines. To examine the functional role that β2m plays in pancreatic cancer, we used siRNA specific for β2m to decrease its expression in the mentioned panel of pancreatic cancer cell lines and evaluated migration by transwell assay. Our results showed that the migration of the tested pancreatic cancer cell lines significantly decreases when β2m expression is reduced. Furthermore, we found that when β2m levels are downregulated, there are corresponding decreases in the levels of the HLA-A and -B heavy chains and in the expression of amyloid precursor-like protein 2 (APLP2). Previous research from our laboratory has shown that β2m affects APLP2/MHC association and that reducing expression of APLP2 slows pancreatic cancer cell migration. Additionally, our current research demonstrated that downregulation of β2m expression reduces the steady-state level and the half-life of APLP2. In conclusion, our results indicate that β2m promotes the migration of pancreatic cancer cells and suggest that this effect may be mediated through stabilization of the HLA class I heavy chain and, secondarily, APLP2. These studies thus provide evidence of β2m as a potential target for novel therapies directed against pancreatic cancer. Citation Format: Bailee Sliker, Cassie Liu, Brittany Poelaert, Benjamin Goetz, Joyce C. Solheim. Beta 2-microglobulin promotes human pancreatic cancer cell migration [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B028.