Determining the Role of Age-Related Signals in GEP-NET Development

In the evolving landscape of oncology, duodenal gastrinomas present a unique biological puzzle where aging, inflammation, and cellular exhaustion converge. In a conversation with CancerNetwork®, Suzann Duan, PhD, assistant professor in the School of Pharmacy & Pharmaceutical Sciences at UC Irvine, discussed the intricacies of these neuroendocrine tumors (NETs), moving beyond simple transcriptomics to uncover how the tumor microenvironment (TME) actively orchestrates disease progression. This was foregrounded by her receipt of a grant from the Neuroendocrine Tumor Research Foundation (NETRF) for her research seeking to determine the role of aging in gastroenteropancreatic (GEP)-NETs.¹

Central to Duan’s research is the discovery that cytokines such as IL-17B, TNF-α, and IL-6 are far more than inflammatory bystanders. Instead, they are key components of the senescence-associated secretory phenotype (SASP). By utilizing 3D organoid models, her team demonstrated that these cytokines can actively drive neuroendocrine differentiation, essentially “reprogramming” normal tissue. This age-related profile offers a biological explanation for the rising incidence of these tumors in older populations, particularly as the TME becomes increasingly “immunologically cold.” Duan further highlighted that physical stromal barriers often form around tumors, which exclude immune cells.

Moreover, she touched upon the paradoxical application of menin-MLL inhibitors. While these are typically used to disrupt oncogenic signaling in leukemia, Duan’s work suggests they may serve a restorative function in NETs by stabilizing mutated menin proteins and rescuing tumor suppressor activity. As these menin-restorative therapies move toward the clinic, her group is carefully monitoring potential adverse effects on normal endocrine function given menin’s ubiquitous role across different tissues.

From the emerging role of Hedgehog signaling to the complexities of neuro-immune communication, Duan’s insights shed light on what she described as a historically understudied field. By framing NETs not just as static growths but as dynamic products of an aging landscape, her work may signal the development of precision therapies that address the specific stromal and proteostatic stresses of the older adult GEP-NET population.

CancerNetwork: In your recent spatial profiling work, you identified that the expression of cytokines like IL-17B, TNF-α, and IL-6 in duodenal gastrinomas may be linked to the SASP. How does this age-related profile actively promote neuroendocrine differentiation?

Duan: [I will] provide some context into why we were even interested in looking at cytokine networks in these cancers. Initially––this was a few years ago––we performed some transcriptomic studies on duodenal gastrinomas, as well as some other types of NETs, including pancreatic NETs. [We identified] upregulated expression of some of these cytokines, like TNF-α, within that signaling pathway, a bit of IL-6, Staph-3 signaling, and IL-17B.

These are all upregulated in those duodenal gastrinomas at the transcript level, and with any transcriptomic study, you then pause and try to see what the functional implications of those changes at the gene level are. It turns out that there’s been quite a bit of literature looking at upregulated cytokines within these cancers, both circulating within the blood and then also within the tumors themselves. Some of that early work showed that these cytokines could induce the expression of neuroendocrine genes and markers. Taking that into consideration, we wanted to validate that, and we were able to generate 3D organoid models from normal human duodenal tissue. We exposed them to some of these cytokines, like TNF-α [and] IL-17B. Indeed, we did validate that those cytokines could upregulate the expression of neuroendocrine markers. That indicated there was a functional role for these cytokines in activating that neuroendocrine differentiation pathway.

In terms of bringing in the senescence aspect, we also know that these tumors can express certain senescence markers, like p16 or p21, and they can present as slow-growing, slow-cycling tumors, which is [like] a puzzle. At some point, these tumor cells started to proliferate, and then they slow down, and they’re almost in some type of quiescent, potentially senescence state. We then thought that maybe these cytokine profiles are related to a senescence phenotype, particularly the SASP. We also know that is increased in aging individuals and could potentially be a biological reason for why increased age contributes to potentially higher incidence of these tumors.

Your research highlights that duodenal gastrinomas often exist in an "immunologically cold" microenvironment. Does immunosenescence contribute to this exclusion, and could this explain the rising incidence of these tumors in older adult populations?

We’re interested in investigating that aspect from the perspective of, “are the actual tumor cells themselves taking on a senescent phenotype, or is this more driven from a senescent stroma?” [This], of course, includes the immune landscape. There are 2 angles to that. In terms of the amino senescence, our lab is interested in looking at menin, which we know functions as a classic tumor suppressor protein in these tumors. But there’s been some prior evidence…on [how] certain immune cells can drive more of a senescent phenotype, and that could potentially be a reason why we’re seeing changes. Really, when we histologically examine these tumors, we see a lot of stromal infiltration and reactivity. Looking at the histology, you see this physical barrier forming around the NETs. You can imagine how that could be preventing immune cells from infiltrating into the tumor, and that could be another reason why we see an immunologically cold tumor.

Does the proteostatic stress associated with aging exacerbate protein turnover in tumorigenesis, and could targeting the degradation pathway be a viable strategy alongside menin-MLL inhibition?

I have not come across much literature examining that, but it could be justified. We know that proteostasis is altered in other solid malignancies. Typically, we associate it with tumor cells with greater genomic instability, and this can increase rapid proliferation, which then leads to protein destabilization. NETs are potentially different. If they’re slower growing tumors, whether they might mimic a similar proteostatic phenotype is a good question [that is] certainly worthy of investigation.

With menin-MLL inhibitors currently in phase 2 clinical trials for other indications, what is the specific biological rationale for why these drugs would be particularly effective in well-differentiated grade 1/2 NETs?

This question has been posed several times before. It’s a bit counterintuitive. We know that menin-MLL inhibitors were originally identified for these leukemias, where menin is a co-oncogene as a proteogenic function in those cancers. Targeting menin makes sense. When you have the reverse or opposite function in an endocrine cell or a NET, why would targeting menin be beneficial?

This follows work that was published during my time [with] Juanita L. Merchant, MD, PhD, at the University of Arizona. We published this work back in 2023 and saw that when you delivered a menin inhibitor to certain types of endocrine tumor cells, you could essentially stabilize the expression of menin proteins, specifically mutated menin proteins that resulted from clinically relevant mutations.² This idea is something that we’re actively pursuing in my group; maybe some of these menin inhibitor compounds can rescue or restore mutated menin function and then help in terms of suppressing tumor development.

How does the age-related decline in neuro-immune communication alter the signaling between the tumor and its surrounding stroma, particularly regarding the pro-neural factor IL-17B?

The short answer to that question is we don’t know yet. It’s definitely something worth pursuing, especially given that we’re seeing so many other studies revealing an important role for neurons…in the tumor microenvironment. Potentially, IL-17B being produced by a NET could be converting or reprogramming adjacent cells to take on a neuronal phenotype. That could, in turn, be causing changes to the tumor microenvironment to cause immune exclusion. In a paper in Cell earlier this week, [investigators] were looking at triple-negative breast cancer, and sensory neurons were essentially stimulating the stromal fibroblasts to create an immune-exclusive environment.³ We haven’t looked at these things in NETs, but it would be exciting [to do so].

In translating menin-restorative therapies to the clinic, particularly for older patients who may have multiple comorbidities, what potential adverse effects on normal endocrine function are you most closely monitoring in your preclinical safety profiles?

That is relevant, given that menin is ubiquitously expressed in different cell types and tissues. Certainly, it’s important to bring in the immune landscape knowing that menin has a completely different function in those cell types. But in terms of preclinical safety, we’re not quite there yet in terms of investigating that, but it is certainly worthy of consideration.

Is there anything else that you would like to highlight that we might not have covered?

We know that [NETs] have been historically excluded [and] understudied, and I’m so glad that they are gaining more attention and traction within the medical and research field. I am extremely grateful for organizations like NETRF for supporting research that my lab is doing and advocating for patients and care providers within that space. It drives home the importance of what we do in the lab and at the bench. Lastly, I want to highlight that we just had a paper accepted, which I’m hoping will be in press [soon]. Some of that work is looking at the role of Hedgehog signaling in these tumors. There’s a potential role for that within the aging landscape as well.

References

1. NETRF 2025 BTSI awardee spotlight: advancing GEP-NET research with Suzann Duan, PhD. News release. Neuroendocrine Tumor Research Foundation (NETRF). August 18, 2025. Accessed February 17, 2026. https://tinyurl.com/2s4jynta
2. Elvis-Offiah UB, Duan S, Merchant JL. MENIN-mediated regulation of gastrin gene expression and its role in gastrinoma development. FASEB J. 2023;37(5):e22913. doi:10.1096/fj.202201809RR
3. Zhang SW, Wang H, Xiao Y, et al. Sensory neurons drive immune exclusion by stimulating a dense extracellular matrix in the breast cancer tumor microenvironment. Cell. Published online February 5, 2026. doi:10.1016/j.cell.2026.01.001