Pancreatic cancer: Advances and challenges

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.

Figure 1:. Initiation and Progression of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) forms from the exocrine tissue of the pancreas. Acinar and ductal cells have both shown the potential to serve as cells of origin for PDAC upon acquisition of oncogenic mutations and/or loss of tumor suppressor function. Activating mutations in the oncogene KRAS are found in the two most commonly observed PDAC precursor lesions: pancreatic intraepithelial neoplasia (PanINs) and cystic lesions termed intraductal papillary mucinous neoplasm (IPMNs). In addition to KRAS mutations, activating mutations in the gene encoding for the G-protein alpha subunit Gαs (GNAS) and loss of function of the tumor suppressor gene RING-type E3 ubiquitin ligase (RNF43) are associated with IPMNs. As these precursor lesions progress from low grade to high grade lesions, loss of the tumor suppressor CDKN2A or components of the SWI/SNF chromatin-remodeling complexes are observed. Further deletion or inactivating mutations of tumor suppressor genes SMAD4 or TP53 accompany the advancement of precursor lesions to PDAC. PDAC has also been classified into several RNA-based transcriptomic subtypes. “Classic” and “Basal-like” have emerged as two consensus groups, with a third “Hybrid” capturing those with overlapping features.

Figure 2:. Cancer-associated Fibroblast Origin and Heterogeneity.

Several types of fibroblasts are present in both the normal pancreas (left) and PDAC (right). Normal pancreatic fibroblast populations include pancreatic stellate cells (PSCs), Gli1⁺ fibroblasts, Hoxb6⁺ fibroblasts, Fabp4⁺ fibroblasts, CD105⁺ fibroblasts, pericytes, and WT1⁺ mesothelial cells that encase the organ. Within PDAC, cancer-associated fibroblast (CAFs) populations include myofibroblastic CAFs (myCAFs) associated with collagen deposition, inflammatory CAFs (iCAFs) that associate with macrophages (MΦ), antigen-presenting CAFs (apCAFs), CD105⁺ CAFs, and fibroblast activation protein containing (FAP⁺) fibroblasts. Lineage tracing has demonstrated that PSC-derived CAFs make up less than 10% of the overall number of CAFs and have roles in promoting tumor growth and inflammation. Gli1⁺ CAFs can account for nearly half of all the fibroblasts in pancreatic cancer, with roles in depositing matrix and modulating immune response. Hoxb6-derived CAFs are infrequent and have no known function akin to their role in embryonic pancreas growth. The number of mesothelial-derived CAFs is unknown, as is their function outside of a potential antigen presentation role.

Figure 3:. Immune Interactions in Pancreatic Cancer.

A network of interactions between fibroblasts, cancer cells, and immune cells create an immune-suppressive tumor microenvironment. Monocyte-derived suppressor cells (MDSCs) that inhibit CD8 cytotoxic T cells are polarized by chemokine ligands (CCLs) and interleukin 6 (IL6) from inflammatory cancer-associated fibroblasts (iCAFs), and by CXCL12 from fibroblast activation protein containing (FAP⁺) fibroblasts. Granulocyte macrophage colony-stimulating factor (GM-CSF) released by neoplastic cells also polarizes tumor-associated macrophages that inhibit CD8 T cells. Further, T regulatory cells (Tregs) inhibit CD8 T cells, and supply TGF-β that allows for myofibroblastic cancer-associated fibroblast (myCAF) activation. IL17 and IL22 released by Th17 and Th22 cells, respectively, provide pro-growth signals to cells to PDAC cells via binding to cognate cell surface receptors. Dendritic cells are sparse in pancreatic cancers, and those present are of low quality, further contributing to the lack of an effective anti-tumor adaptive immune response to PDAC.

Figure 4:. Altered Metabolism and Metabolic Interactions of Pancreatic Tumors.

A. Pancreatic ductal adenocarcinoma (PDAC) cells have increased glucose consumption to fuel glycolysis and anabolic metabolism from glycolytic intermediates. These include upregulation of the hexosamine biosynthetic pathway (HBP) to produce O-GlcNAc needed for protein glycosylation, and the pentose phosphate pathway (PPP) to produce nucleotides. PDAC cells also take advantage of a re-wired malate-aspartate shuttle (MAS) to fuel mitochondrial metabolism and oxidative phosphorylation (OXPHOS), and intermediates from the tricarboxylic acid (TCA) cycle provide synthetic metabolic building blocks. In addition to creating new biosynthetic material, PDAC cells recycle proteins and organelles through autophagy, and obtain extracellular materials through a non-specific fluid uptake process known as macropinocytosis. B. Many metabolic interactions shape the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) provide alanine (Ala), lysophosphatidic acid (LPA), and exosomes loaded with metabolites to PDAC cells. The nutrient support of CAFs is at least in part fueled by macropinocytotic uptake of extracellular materials. PDAC cells metabolize extracellular matrix deposited in the TME to obtain hyaluronic acid (HA) to fuel GlcNAc pools and collagen to support proline (Pro) pools. Tumor-associated macrophages (TAMs) are polarized by signals including lactate and granulocyte macrophage colony-stimulating factor (GM-CSF) from PDAC cells. TAMs release deoxycytidine, also released by CAFs, that directly competes with the anti-metabolite chemotherapy gemcitabine. In addition, neurons in PDAC tumors can share serine (Ser), which is used to support mRNA translation.

Figure 5:. Hallmarks of Pancreatic Cancer Therapy.

Five major themes have emerged as priorities to improve pancreatic cancer treatment. Genomic Alterations: Numerous approaches to directly target mutant RAS are entering clinical care and sequencing can identify alternative genetic drivers that can be exploited to effectively treat smaller subsets of patients. Metabolism: The rewired metabolism of pancreatic cancer cells presents opportunities to selectively target neoplastic cells. Scavenging, recycling, and metabolic crosstalk programs engaged to deal with nutrient dysregulation in pancreatic tumors can be blocked to starve cancer cells and prevent therapy resistance. Tumor Microenvironment: The characteristic pancreatic tumor microenvironment can be remodeled to increase drug perfusion by targeting stromal fibroblasts or the matrix directly, however, these strategies must not remove the barrier to cancer cell migration. Immunotherapy: Disruption of interactions between cell populations and reprogramming of myeloid cells in pancreatic tumors can relieve immune suppression. Decreases in immune suppression will likely need to be coupled with efforts to increase antigen presentation, increase cytotoxic T cell infiltration into tumors, and prevent their exhaustion. Innovative Clinical Trial Design: Clinical studies testing need to prioritize approaches most likely to succeed, continuously reassess patients on the trials using molecular correlatives, and quickly transition patients who are not responding onto different treatments. Importantly, these priorities are not mutually exclusive, and best probability of success lies in methods that will address multiple themes described above.