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Two papers examine the influence of different stem cell characteristics on tumorigenesis in an organ-specific and age-associated manner, continuing the debate on the influence of intrinsic and extrinsic factors on cancer risk.

Doc number: 22

Two papers examine the role of cell competition in tumorigenesis.

Abstract Disclosure: M. Jakubowski: None. S. Yaqoob-Krzystofiak: None. C. Burke: None. J. Bellizzi: None. J. Costa: None. A. Arnold: None. Familial isolated primary hyperparathyroidism (FIHP) is a form of primary hyperparathyroidism (PHPT) in which there is familial clustering of individuals with tumors in the parathyroid glands, which secrete inappropriately elevated amounts of parathyroid hormone (PTH) leading to dysregulated calcium homeostasis. The genetic cause of FIHP in most kindreds is unknown. In vitro activating germline variants in GCM2, encoding an eponymous transcription factor critical for parathyroid gland development, were reported in a subset of FIHP kindreds, but their pathogenicity, penetrance, and implications for clinical management are uncertain. One such variant, I383M, was associated with a severe phenotype, including parathyroid carcinoma, in one kindred. We sought to evaluate the effects of GCM2 I383M on PHPT and parathyroid tumorigenesis in a mouse model. Genetically engineered mice with a Gcm2 I383M mutation were compared to wildtype littermate controls. Gcm2 I383M mutant mice were viable, developed normally and appeared healthy. Mice were followed to a terminal timepoint of 18 months, at which parathyroid tissue was excised and blood was collected. Mice were evaluated for biochemical hyperparathyroidism and parathyroid tumorigenesis. Serum calcium, PTH, parathyroid gland volume and parathyroid cell proliferation, as measured by Ki67 immunostaining, were indistinguishable between Gcm2 I383M mutant and wildtype littermates. Thus, our results demonstrate that Gcm2 I383M mutant mice do not develop PHPT or parathyroid tumors. However, as our laboratory has recently demonstrated, another Gcm2 activating variant (Y392S, equivalent to human Y394S) was similarly insufficient to drive PHPT on its own but could cooperatively enhance parathyroid tumorigenesis in a mouse model of PHPT driven by parathyroid-specific overexpression of cyclin D1, suggesting this variant might function as a mild-to-moderate predisposition allele, rather than a tumor driver. Whether GCM2 I383M might similarly serve as a predisposition allele for PHPT merits further investigation. Presentation: Saturday, July 12, 2025

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.

Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-β plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF-β elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF-β signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF-β-induced growth arrest, and TGF-β functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF-β further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF-β signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF-β-induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions.