Pancreatic adenocarcinoma (PDAC) is often characterized by substantial amounts of fibrosis, and how these stromal components affect metabolite availability is not fully understood. Zhu et al. now show that cancer-associated fibroblasts consume branched-chain amino acids (BCAAs) at high levels but release corresponding branched-chain α-ketoacids that support PDAC cell growth.
The ‘seed and soil’ hypothesis has provided a convenient model to characterize the relationship between cancer cells and the surrounding stroma. Cancer-associated fibroblasts (CAFs), immune cells and other components secrete pro-growth mediators (such as growth factors and inflammatory cytokines) that stimulate and nourish primary or metastatic tumours. But what happens when the soil steals nutrients from the seed?
PDAC, the main form of pancreatic cancer, is a devastating disease with one of the poorest 5-year survival rates among all cancers. Currently available chemotherapeutics have been demonstrated to be largely ineffective against PDAC, thus prompting a search for novel targets. Cancer metabolism has been of general interest in recent years, and the study of PDAC has been particularly compelling, given the frequent extensive desmoplasia in tumours, and a host of mechanisms used to scavenge nutrients. Specifically, regions of PDAC tumours can consist of as much as 90% stroma and are poorly perfused in general1. When the nutritional needs of PDAC tumours are not met, mechanisms such as macropinocytosis and lysosomal degradation are used to non-specifically import, break down and free up metabolites. Whether PDACs seek out specific nutrients, and how they are obtained, is an active area of research. Since the observation that elevated serum levels of branched-chain amino acids (BCAAs) are predictive of the development of PDAC2, there has been particular interest in these metabolites.
BCAAs consist of leucine, isoleucine and valine, and are essential amino acids that cannot be synthesized de novo in humans. Like other amino acids, BCAAs are incorporated into proteins and can be released after protein breakdown. In the context of cancer, this breakdown can occur both locally within the tumour microenvironment and systemically (for example, during cachexia). BCAAs can also be catabolized, thus ultimately producing succinyl-CoA, acetyl-CoA and propionyl-CoA. During catabolism, BCAAs are first deaminated by cytosolic (BCAT1) or mitochondrial (BCAT2) enzymes, which generate branched-chain ketoacids (BCKAs). Importantly, this step is completely reversible, and BCAAs can be generated by re-amination of BCKAs (Fig. 1). The remaining enzymatic steps that catabolize BCKAs and downstream metabolites are unidirectional.
Against this backdrop, Zhu et al.3 have now observed that stroma-rich tissues, particularly, stroma-rich pancreatic tumours, have high expression of BCAT1. Through RNA sequencing (including single-cell data), immunohistochemistry and laser-capture microdissection, they show that the high BCAT1 levels in these tumours are driven by elevated expression in stromal cells, predominantly CAFs. Notably, the authors have found that both normal pancreatic ductal cells and PDAC cells have relatively low levels of BCAT1 but high levels of BCAT2, in agreement with data from two very recent publications4,5. Interestingly, by performing enzyme activity assays, the authors have shown that CAFs convert BCAAs to BCKAs at a rate three times faster than that in PDAC cells3.
On the basis of these data, the authors postulated that the flux and handling of BCAAs might be distinctly different in regions of pancreatic tumours enriched with CAFs. Removal of BCAAs from cell culture media mitigated the growth of PDAC cells, but, unexpectedly, coculture with CAFs completely restored proliferation. The authors observed that supplementing BCKAs in BCAA-free medium restored PDAC proliferation, and CAFs secreted substantial amounts of BCKAs. The BCKAs were taken up by PDAC cells and were re-aminated into BCAAs and incorporated into proteins, as well as further catabolized to sustain pools of downstream metabolites (Fig. 1). Overall, the data suggest that in conditions in which BCAAs are scarce, PDAC cells can use CAF-secreted BCKAs for growth and survival and indeed may prefer BCKAs as substrates in certain situations. The BCAAs may be scarce as a direct result of the presence of CAFs, because the CAFs appear to outcompete PDAC cells for the BCAAs (Fig. 1).
The metabolic handling of BCAAs locally and systemically remains an evolving field, and the work by Zhu et al. comes on the heels of some interesting complementary publications. Normal pancreatic tissue is now known to have one of the highest rates of BCAA consumption and catabolism in the body6. This aspect appears to be further accentuated in PDAC and precursor lesions (pancreatic intraepithelial neoplasia) because of enhanced BCAT2 protein expression4,5. Knockdown of BCAT2 suppresses the proliferation of PDAC cells in vitro5, and knockout of BCAT2 or dietary BCAA restriction hampers the development and growth of tumours in vivo4. Importantly, the models analysed in these publications have no, mild or moderate desmoplasia. In other words, in conditions in which stromal cells are scarce and BCAAs are relatively abundant, PDACs appear to be ready and able to take up and use or catabolize BCAAs. However, when stromal cells are abundant and BCAAs are relatively scarce, PDAC cells become conditionally reliant on BCKAs. In both situations, BCAT2 is highly important, converting BCAAs to BCKAs and vice versa.
The data from these publications may also be applicable to other cancers. A range of cancers are now known to display elevated BCAT1 and/or BCAT2 expression7, although whether this elevation has a functional role remains to be investigated in most cancers. Mechanistically, altered BCAA catabolism in cancer has been shown to support protein synthesis3, regulate the intracellular levels of key metabolites5,8 and stimulate activity of the mTORC1 complex7,9,10. Intriguingly, enhanced BCAT1 expression has been observed in both chronic myeloid leukaemia and acute myeloid leukaemia, yet chronic myeloid leukaemia has a net BCAA-to-BCKA flux, whereas acute myeloid leukaemia has a net BCKA-to-BCAA flux8,9. What regulates this net flux, and whether it is fixed or can be reversed under certain conditions, remains ill defined. The data from Zhu et al. and other groups support the notion that enhanced BCAT expression may be beneficial by providing metabolic flexibility, thus allowing cancer cells to thrive in varying nutritional environments.
Although the experiments performed by Zhu et al. experiments are detailed and extensive, there remains a lack of direct evidence that this transfer of BCKAs from CAFs to PDAC cells indeed occurs in tumours in vivo. Despite being technically challenging, strategies exist to examine such cross-talk1. Refinement of in vivo models and heightened sensitivity of analytical methods will be helpful. Why stromal cells, and particularly CAFs, require such high levels of BCAA catabolism is also interesting yet unclear. With minimal proliferation3, BCAAs are apparently not needed for protein synthesis, and BCKAs are released rather than oxidized. Whether blocking BCAA catabolism in CAFs alters their phenotype and can be exploited for therapeutic purposes would be an interesting topic to explore. Finally, a direct comparison of BCAA handling in stroma-rich and stroma-free tumours would also help to consolidate the data from recent publications and build a broader, more cohesive model.
Cannon, A. et al. Genes Cancer 9, 78–86 (2018).
Mayers, J. R. et al. Nat. Med. 20, 1193–1198 (2014).
Zhu, Z. et al. Nat. Metab. https://doi.org/10.1038/s42255-020-0226-5 (2020).
Li, J. T. et al. Nat. Cell Biol. 22, 167–174 (2020).
Lee, J. H. et al. Exp. Mol. Med. 51, 1–11 (2019).
Neinast, M. D. et al. Cell Metab. 29, 417–429.e4 (2019).
Ericksen., R. E. et al. Cell Metab. 29, 1151–1165.e6 (2019).
Raffel, S. et al. Nature 551, 384–388 (2017).
Hattori, A. et al. Nature 545, 500–504 (2017).
Gu, Z. et al. Cancer Discov. 9, 1228–1247 (2019).
The authors declare no competing interests.
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Ericksen, R.E., Han, W. Give and take: competition for BCAAs in the tumour microenvironment. Nat Metab 2, 657–658 (2020). https://doi.org/10.1038/s42255-020-0239-0