IGF-1 and GLP-1 Shape Liposarcoma Development, Presenting Potential Targets

The rarity and variety in sarcoma subtypes make developing effective treatment a significant unmet need in oncology, but now, research that leverages patient-derived multidimensional, single nucleus sequencing data is seeking to unravel the mechanisms behind cancer cell dedifferentiation, a significant prognostic marker, within the transition from well-differentiated to dedifferentiated liposarcoma. One of the key pathways under investigation may identify a way to use commercially available GLP-1 receptor agonists to shape the tumor microenvironment.

“We have this opportunity with a host of FDA-approved drugs now that target this pathway, that have been proven safe over the last few decades that they’ve been in use,” said Erica Pimenta, MD, PhD.

In an interview with Targeted Oncology, Pimenta, an Instructor at Harvard Medical School and physician-scientist at Dana-Farber Cancer Institute, discussed the goals and key findings from her and her colleagues’ research into IGF-1 and GLP-1 signaling pathways. Pimenta detailed a “molecular switch” involving the epigenetic silencing of the PPAR-γ2 isoform, which drives dedifferentiation, and explores the potential of IGF-1 receptor-targeted antibody-drug conjugates (ADCs). Furthermore, she discusses the intriguing finding that GLP-1 receptor agonists may induce markers of terminal differentiation by modulating intracellular calcium flux. These insights are currently being translated into clinical frameworks to determine if metabolic modulation can improve immunological responses and outcomes for patients with resectable disease.

Targeted Oncology: What are the main challenges of treating sarcomas vs other cancers?

Erica Pimenta, MD, PhD: Sarcomas in general are much rarer than their carcinoma counterparts. Carcinomas, as we know, come from the epithelial layer. They’re exposed to a lot of the environmental carcinogens that we think about, like smoking in lung cancer, but sarcomas are connective tissue cancer, so they’re already shielded from a lot of those environmental factors, which means we understand a lot less about what causes them and what causes them to be aggressive. Because there are so many kinds of connective tissues, each individual subtype of sarcoma is quite rare, and that rarity poses 2 practical challenges. The first is that we don’t have hundreds of patients with which to run clinical trials for each individual sarcoma, and so we don’t understand a lot about how treatments affect patients and even the natural history of some of these diseases. The second is because we don’t have hundreds of patients at an institution with one kind of sarcoma, we have less of an opportunity to make robust model systems that faithfully recapitulate the disease that we see.

With that rarity comes this opportunity to really learn more about the biology of the disease. Our work, which uses multidimensional data from patient tumors through computational analysis of sequenced tumors, really only was possible with the advent of single nucleus sequencing. My work focuses on finding these big axes of deviation, so differences in clinical behavior [and] differences in outcomes within a sarcoma subtype, then getting a curated cohort of patient samples, applying single nucleus sequencing to really start to unravel what is the biology underlying that difference.

What cellular pathways in liposarcoma are studied in your published findings?

One of the fundamental questions of cancer biology is, what causes cancer cell dedifferentiation? Whether [it’s] sarcoma or carcinoma, we know that that’s a bad prognostic sign for a patient. Sarcomas are really interesting because to answer questions about sarcoma biology, you have to answer these hard questions. Cancer cell dedifferentiation was a particular interest of mine. Within sarcomas, there’s a subtype called liposarcoma, which has 2 subtypes within it, well-differentiated and dedifferentiated, and a well-differentiated tumor can spontaneously become dedifferentiated.² It’s this unique opportunity to study dedifferentiation within a tumor type that we now know has similar genomics, so this is not a genomic event. We applied single-nucleus multiome sequencing so we could look at the epigenome and the transcriptome.

…Both the epigenome and the transcriptome pointed to 2 interesting pathways in liposarcoma.¹ One is the absence of IGF-1 signaling in dedifferentiated liposarcoma, but it’s very present in well differentiated [liposarcoma]. The second, which was intriguing to us, was the fact that dedifferentiated cancer cells were poised to respond to GLP-1 signals, and so that came out in the epigenomic data, and those are the 2 pathways that we’ve focused on.

What were your findings on the IGF-1 signaling pathway?

Liposarcoma is derived from a pre-adipocyte. In normal adipose tissue, there’s this well-defined path where IGF-1 is the physiologic ligand that starts differentiation through the receptor, kicks off differentiation through PPAR-γ transcription factor activity, and then you turn on the downstream genes that make an adipocyte. We went step by step and we found that simply restoring IGF-1 was not sufficient to cause differentiation. You can add it back, and these cells don’t really care. We found that the receptor is abundantly overexpressed on the cell surface but is not dysfunctional. Then we turned our attention to PPAR-γ, and PPAR-γ has 2 isoforms. The first is not specific to adipose tissue. It’s present in every cell. The second is specific to adipose tissue. It turns out that isoform 1 has to become activated and bind to the promoter of isoform 2 to start adipogenesis.

We became curious about what was happening with the isoforms in dedifferentiated liposarcoma. What we found was that the dedifferentiated cells never had any PPAR-γ2, so that second isoform is just missing. We also showed this in additional human tumor samples. When we establish cell lines that we’ve forced to express PPAR-γ2, they differentiate, which was a really cool and striking result. Then we could use the multiome data; go back into the human system, and we found that this the promoter region of PPAR-γ2, specifically, is inaccessible, so that chromatin is compacted only in that genomic region across the PPAR-γ gene in dedifferentiated liposarcoma. I’m excited about this result, because I think we found the molecular switch that dictates whether you’re going to be this nonmetastatic, well-differentiated tumor or this very metastatic, dedifferentiated tumor.

We’re doing work now to try to understand what is the mechanism of that chromatin compaction, and can we switch that back on. Can we turn on this isoform to allow differentiation, akin to how we treat APML [acute promyelocytic leukemia], by giving them a ligand that allows differentiation? That’s our IGF-1 pathway story so far, and there’s more to come once we figure out the mechanism of chromatin compaction.

How did you test if IGF-1 could be targeted by a drug?

Because I’m also a clinician, I always ask, is there something useful here now? When IGF-1 physiologically starts to bind the receptor and turn on adipogenesis, like most things in our bodies, there’s a balance. You dampen the level of the receptor so that you’re not overdoing that signaling…which means in dedifferentiated liposarcoma, you’re never getting that negative feedback, so you’re just expressing IGF-1R. We found that across our cell lines and in our human tissue, you see overexpression, probably super-physiologic levels of the protein at the cell membrane, which…you can try to target with an ADC. We mimicked an ADC that’s in clinical trials in Europe now and found that across almost every dedifferentiated liposarcoma cell line, we get selective cytotoxicity from an IGF-1 [receptor] targeted ADC.

Can you talk more about your research into the GLP-1 pathway?

That research is very actively ongoing, but was really intriguing and exciting to us. We were surprised to see that the dominant epigenomic program in dedifferentiated liposarcoma was this pathway called GLP-1–induced insulin secretion. That was curious to us, and so we looked under the hood and wanted to figure out what genomic regions were causing that enrichment.

We found that they were genes in the ITPR and the ADCY family. These genes have one shared function in common, which is that they help regulate levels of calcium within the cell. I went back and tried to understand where this pathway was derived. This pathway was discovered in pancreas β-cells. So when GLP-1 binds its receptor on a pancreas β-cell to induce insulin secretion, it does so through changes in calcium flux within the cell: differences in intracellular membrane potential. It uses those genes, ITPR and ADCY, to help do that.

I tried to understand what GLP-1 was doing in normal adipocytes, and there’s actually not a lot of literature about what GLP-1 or GLP-1 agonists do to a normal adipocyte. We know a lot about how it changes adipose tissue systemically, but not the direct effects on the cell, so I couldn’t start making hypotheses from what we knew there.

Then I did a little digging on to what those genes, the ITPRs [and] the ADCYs, do within adipocytes. I learned through this project that calcium flux is extremely important for adipose differentiation. It’s a major component that is necessary, and it uses those same genes. Remembering that nature is not wasteful, it made sense that maybe GLP-1 is acting through these same intermediate genes in normal pre-adipocytes to induce calcium flux and at least invoke some of the adipose differentiation program. So, we added an old-fashioned GLP-1 receptor agonist to our dedifferentiated liposarcoma cells, and we found that this was the only pharmacologic agent that we could add that would increase the expression of markers of terminal differentiation. These are not the terminal markers of differentiation that are specifically PPAR-γ2 dependent. It’s a whole host of other necessary downstream genes. Now we’re excited about the fact that we may have found either a noncanonical route to differentiation, or something that skews those cells towards a more differentiated state, even if it doesn’t complete the process- [and] does that translate to less metastatic potential in patients?

How are you applying this to use GLP-1 receptor agonists in patients with liposarcoma?

One of the exciting parts about working at a high-volume sarcoma center with lots of clinical trialists is we are constantly talking about our different interests, and we have this opportunity here to do 2 or 3 things. The first is…there aren’t a lot of model systems that faithfully recapitulate liposarcoma. We do have a couple of PDXs [patient-derived xenograft models], but they don’t have any immune system. From the carcinoma literature, we can expect that GLP-1R agonists in patients shape the tumor microenvironment and their peripheral immune cells. We’d be missing that if we went into the mouse system and tried to understand the GLP-1–induced changes.

We also have this opportunity with an FDA-approved host of drugs now that target this pathway that have been proven safe over the last few decades that they’ve been in use. There’s this alignment to things that might work in our favor. When we treat patients with dedifferentiated liposarcoma, if that tumor is resectable…that’s our cure. That’s our mainstay of treatment. We have an opportunity with our surgical colleagues to take biopsy samples of a patient at baseline, and then perhaps when they go for resection, or if they agree to additional biopsies, after a period of time on a GLP-1 receptor agonist, we can look and ask the question, are the changes that we’re seeing in the cell lines actually happening in people?

The changes we look for are these changes in these differentiation markers. But also, we can broaden the scope of it and ask questions about the immune system, and does this help shape the immunological response in dedifferentiated liposarcoma, where we know immunotherapies have had modest effects so far, but can we augment that effect by modifying the metabolic state of the tumor? We’re excited about that. We’re drafting that now and hope to open that soon.

What other unanswered questions in sarcoma are you interested in?

I’m most excited about the small signal that we see that for some patients that currently available immunotherapies can work. I’ll state that ‘work’ means we’ve stabilized the tumor; they’re not curing patients like we see in melanoma. But there’s a hint that if the right type of cell is there, maybe we can bolster the immune response. In particular, that immunological aim of the study of the GLP-1 study is exciting to me.

Second, I’m excited to see if this differentiation framework that we’re learning about, whether it be chromatin compaction at a specific protein isoform or alternate differentiation pathways, how far that expands. I know it will apply to other sarcoma subtypes, but I’m also excited that it may help us answer questions about, for example, sarcomatoid renal cell carcinoma or sarcomatoid lung cancers, these hard-to-treat diseases that straddle both disease groups. I firmly believe that figuring things out in the sarcoma space are going to have far-reaching implications if we can actually dissect the biology. There’s lots to be done in the world of sarcoma; liposarcoma just happens to be a really nice model for dedifferentiation.

REFERENCES

1. Pimenta EM, Garza AE, Camp SY, et al. Epigenetic dysregulation of metabolic programs mediates liposarcoma cell plasticity. Sci Transl Med. 2026;18(833):eadw4689. doi:10.1126/scitranslmed.adw4689

2. Amin-Mansour A, George S, Sioletic S, et al. Genomic evolutionary patterns of leiomyosarcoma and liposarcoma. Clin Cancer Res. 2019;25(16):5135-5142. doi:10.1158/1078-0432.CCR-19-0271