Advances in pancreatic cancer research have highlighted the role of non-cancerous neighboring cells in enhancing tumor growth, cancer metastasis, and resistance to therapies. A previous postdoctoral research fellow in the Clinical Research Division at Fred Hutchinson Cancer Center, Dr. Bo Tu, now at the University of Nebraska Medical Center, sought to better understand how cancer cells communicate with neighboring fibroblast cells to foster an environment optimal for pancreatic tumor development. Findings from Dr. Tu and his colleagues identified a signaling axis involving Lin28b and Wnt5a that drives communication between pancreatic cancer cells and tumor associated fibroblast cells via secreted proteins. This work was published in Nature Communications.
Lin28b is an RNA-binding protein with many known cancer-related roles. Dissection of the molecular mechanisms revealed that Lin28b binds to a microRNA, let-7, to limit maturation of this microRNA. In pancreatic cancer, Lin28b-mediated inhibition of let-7 enhances growth and survival of the cancer cells but much of this mechanism is still unclear. Since neighboring fibroblasts are known to contribute to pancreatic cancer growth and survival, the researchers wanted to understand how Lin28b is regulated in pancreatic cancer cells and if Lin28b was involved in the crosstalk between cancerous and non-cancerous cells in the tumor microenvironment. “This study is particularly exciting for demonstrating that expression of the oncofetal gene LIN28B by pancreatic cancer tumor cells can induce Lin28b expression in nearby fibroblasts,” shared Naomi Yamamoto, a graduate student in Dr. Sita Kugel’s lab whose research interests also include understanding Lin28b roles in pancreatic cancer. This recent publication connects the Lin28b RNA-binding protein to crosstalk activity in the tumor microenvironment. “Importantly, the authors identify Wnt5a and Fzd4 as critical modulators of this induced expression and establish Pcsk9 as a soluble factor released by Lin28b high fibroblasts that supports tumor growth,” continued Yamamoto. Wnt5a is a secreted signaling protein that interacts with receptors, in this case Fzd4, present on the plasma membrane of cells. Based on their findings, the researchers propose a working model in which Wnt5a secretion by pancreatic cancer cells activates receptors on neighboring fibroblast cells to induce Lin28b expression. Aligned with known roles of Lin28b-dependent let-7 microRNA inhibition, the researchers found that this inhibition enhances expression of Pcsk9 in neighboring fibroblasts and Wnt5a in pancreatic cancer cells, to facilitate tumor-fibroblast crosstalk and support extensive growth and survival specifically of tumor cells. “Pancreatic cancer is especially well known for being an incredibly [connective tissue dense or] stroma-rich tumor, and a better understanding of how cancer cells can induce and maintain a desmoplastic response [or connective tissue growth] in the tumor microenvironment will help us develop more effective therapies for this deadly disease.”
The crosstalk defined by these studies contributes significantly to the field and our understanding of signaling that drives pancreatic cancer progression. “Notably, this work adds to the work of my mentor, Dr. Sita Kugel,” shared Yamamoto. “Dr. Kugel previously described a subset of Lin28b-dependent pancreatic cancer tumors, which along with this work would allow us to define the exact patients whose tumors have high Lin28b dependent stromal modifications as described in this paper.” Therefore, “Lin28b and similar oncofetal proteins may be useful biomarkers in pancreatic cancer that will aid clinicians in predicting response to therapy.”
The pancreatic cancer tumor microenvironment is complex with enhanced growth and survival signals that challenge the efficacy of implemented therapies. “By profiling the complete secretome of the cancer-associated fibroblasts in their mouse model, Shu et. al. have the data to fully characterize differences in fibroblasts that may also contribute to differential immune responses to subtypes of pancreatic cancer,” shared Yamamoto. With the advent of immunotherapy use in treating cancer, these findings may provide insights into employing this therapeutic approach for treating pancreatic cancer. “Interestingly, Pcsk9 has primarily been used as a target for cholesterol-lowering medications, and its role in tumor progression is under active investigation. Initial studies have found that blockade of Psck9 has improved tumor response to immunotherapy, and it will be interesting to see how fibroblast-secreted Psck9 plays a role in this response.”
Lastly, genetic mutations in the KRAS transcription factor are common in pancreatic cancer. Yamamoto highlighted that “the majority of experiments in this paper are done using a pancreas-specific KRASG12D overexpressing mouse model. Small molecule inhibitors of oncogenic KRASG12D are currently in clinical trials and have been shown by Kemp et al. to rely on T cells for full antitumor effect.” Since the researchers demonstrated an association between high Lin28b expression and CXCL5 cytokine secretion from tumor-associated fibroblasts, it is possible that this immunosuppressive cytokine may impact the ability of T cell recruitment and antitumor effects in the tumor microenvironment. “It will be prescient to see how these inhibitors, which we are all hopeful will be included in the standard of care for patients with pancreatic cancer, would alter the mechanisms described in this paper.” Continued characterization of crosstalk between cells in the tumor microenvironment is needed and will provide insight into the complex variables driving cancer progression and inform on how best to treat pancreatic cancer.
The spotlighted research was funded by the National Natural Science Foundation of China, National Key R&D Program of China, and Peking University.
Shu Z, Fan M, Tu B, Tang Z, Wang H, Li H, Li H, Yuan M, Bai J, Huo S, Wang L, Zhu WG, Wang W, Liu X, Shu S, Zhao Y. 2023. The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium. Nat Commun. 14(1):6885.