Stressing for sugar: a new role of serotonin for glycolysis in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic stroma in the tumor microenvironment. This histologic feature arises from deposition of extracellular matrix that increases tissue stiffness and limits vascularity (1,2). This stromal architecture offers an advantage to tumor cell survival and metastasis via several mechanisms, including secretion of growth factors between stromal and malignant cells, promoting an immune suppressive microenvironment and acting as a physical barrier, limiting access of therapeutic agents (1-4). A recent publication by Jiang et al. explores a novel mechanism whereby desmoplasia is linked to metabolic stress in PDAC cells (5). The authors demonstrate that under metabolic stress, the neuromodulator, serotonin plays a role as an autocrine mediator of PDAC survival and resistance to apoptosis. Using a series of relevant agonists, antagonists and genetic approaches, the authors validated a role for HTR2B, one key receptor for serotonin that regulates the growth and survival of PDAC cells. To further support the relationship between serotonin signaling and tumor progression, they utilized a series of tissue microarrays comprising more than 300 unique PDAC specimens that were obtained from treatment naïve patients. This study links the ability of PDAC cells to metabolize glucose via glycolysis (i.e., the Warburg effect) to a new mechanism that imparts a viability advantage.

Metabolic features of the PDAC tumor microenvironment are regulated by numerous redundant mechanisms. Given these new data, we can now appreciate the serotonin/HTR2B axis as a clever means by which tumor cells can commandeer neuroregulatory pathways in response to metabolic shifts arising from exposure to desmoplastic changes and poor oxygenation. These results are aligned, but still distinct from other reports implying a role for this axis in PDAC. For example, other independent studies have explored the consequences of modulating serotonin receptors (5-HT-1B and 5-HT1D). Namely, down-regulation of these receptors can inhibit proliferation, clonogenicity and invasion of human PDAC cells in vitro.(6) In this report by Jiang et al. (5), it is worth noting the presence of some degree in variability as to the role of serotonin across individual PDAC cell lines. This inability to rescue certain cell lines from apoptosis induced by serum deprivation points to the need for continued study that may highlight key differences that can be used for better understanding the mechanism on an individual level.

It remains important to consider whether this axis plays a role in cell populations aside from malignant PDAC cells. Indeed, serotonin may impact other cells of relevance in the tumor microenvironment. Notably, serotonin has immunomodulatory properties as a regulator of chemotaxis, lymphocyte activation, and cytokine secretion among others (7). This observation is of particular relevance as other cell types including tumor associated macrophages (TAMs) can promote the Warburg effect in PDAC via distinct mechanisms (8), and the TAMs themselves exhibit prominent glycolytic phenotypic properties (9). Serotonin has also been shown to play a role in regulating acinar dedifferentiation in the pancreas following pancreatitis, and may play a role in accelerating the process of acinar-to-ductal metaplasia by facilitating recruitment of type 2 macrophages (10). Finally, understanding the impact of the serotonin/HTR2B axis on pancreatic stellate cells (PSCs) may also lend further insight into dysregulated metabolic features of PDAC tumors. PSC themselves have glucose intolerance (11) and can facilitate cross-talk that results in rewired metabolic networks of PDAC cells. Of particular relevance is the relationship between KRAS-dependent signaling pathways and metabolic properties of these tumors. Prior studies indicate that reprogramming of glutamine metabolism is mediated by oncogenic KRAS to become a major carbon source for survival of tumor cells (12). This mechanism is thought to involve interactions between PSC and PDAC via the IGF1R/AKL axis, which in turn elevates mitochondrial respiration in tumor cells (13,14), PSCs can also support tumor metabolism through autophagic alanine secretion (15). Curiously, some metabolic parameters can also be altered in a paracrine manner via exosome mediated communication (16). These findings highlight a complex metabolic network within PDAC tumors capable of utilizing several nutrients as fuel to withstand the hostile pressures of fibrosis, hypoxia and chronic inflammatory processes.

This new understanding of serotonin in the PDAC microenvironment could catalyze further interest in pharmacologic inhibition of this pathway. While these results (5) certainly support serotonin/HTR2B signaling as a viable target, the authors wisely point out that prior attempts at inhibiting pathways downstream of HTR2B have had limited success in PDAC. Together these data suggest that interference with serotonin might be considered in the context of combinatorial approaches at least in pre-clinical studies for proof of principle data. The pleiotropic actions of serotonin across multiple cellular compartments could also be better characterized through well-designed gain or loss of function studies using genetically manipulated cell lines or animals to dissect its tumor-intrinsic or tumor-extrinsic role. Finally, it may be informative to expand this line of study into tumors from patients who have been previously exposed to chemotherapy as standard of care for their disease. The interactions of ongoing or prior exposure to cytotoxic drugs could potentially impact receptor expression and integrity of pathways that signal in response to serotonin.

Acknowledgments

Thanks to Dr. Matthew Farren for critical review of this editorial.

Funding: This work was supported in part by NIH grants R01 CA208253 and R01 CA228406.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apc.2018.09.03). GBL reports that he served as a consultant for ProDa Biotech, LLC. GBL received research funds through a sponsored agreement with Emory University for clinical trial correlative studies from Vaccinex Inc., from Bristol Myers Squibb, from Merck and Co., and received research support for preclinical studies through a sponsored research agreement with Emory University from Boehringer Ingelheim, outside the submitted work.

Ethical Statement: The author is 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Neesse A, Michl P, Frese KK, et al. Stromal biology and therapy in pancreatic cancer. Gut 2011;60:861-8. [Crossref] [PubMed]
2. Waghray M, Yalamanchili M, di Magliano MP, et al. Deciphering the role of stroma in pancreatic cancer. Curr Opin Gastroenterol 2013;29:537-43. [Crossref] [PubMed]
3. Mace TA, Ameen Z, Collins A, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 2013;73:3007-18. [Crossref] [PubMed]
4. Whatcott CJ, Diep CH, Jiang P, et al. Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer. Clin Cancer Res 2015;21:3561-8. [Crossref] [PubMed]
5. Jiang SH, Li J, Dong FY, et al. Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice. Gastroenterology 2017;153:277-91.e19. [Crossref] [PubMed]
6. Gurbuz N, Ashour AA, Alpay SN, et al. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells. PLoS One 2014;9:e110067. [Crossref] [PubMed]
7. Arreola R, Becerril-Villanueva E, Cruz-Fuentes C, et al. Immunomodulatory effects mediated by serotonin. J Immunol Res 2015;2015:354957. [Crossref] [PubMed]
8. Ye H, Zhou Q, Zheng S, et al. Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma. Cell Death Dis 2018;9:453. [Crossref] [PubMed]
9. Penny HL, Sieow JL, Adriani G, et al. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 2016;5:e1191731. [Crossref] [PubMed]
10. Saponara E, Grabliauskaite K, Bombardo M, et al. Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas. J Pathol 2015;237:495-507. [Crossref] [PubMed]
11. Xue R, Jia K, Wang J, et al. A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front Physiol 2018;9:754. [Crossref] [PubMed]
12. Son J, Lyssiotis CA, Ying H, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013;496:101-5. [Crossref] [PubMed]
13. Fu Y, Liu S, Zeng S, et al. The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma. Mol Cancer 2018;17:62. [Crossref] [PubMed]
14. Tape CJ, Ling S, Dimitriadi M, et al. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation. Cell 2016;165:910-20. [Crossref] [PubMed]
15. Sousa CM, Biancur DE, Wang X, et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 2016;536:479-83. [Crossref] [PubMed]
16. Zhao H, Yang L, Baddour J, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife 2016;5:e10250. [Crossref] [PubMed]