Mikhail G. Kolonin

Glucagon-like peptide-1 receptor agonists (GLP1RAs) have transformed the treatment of obesity and type 2 diabetes, but their effects extend beyond metabolic regulation. Emerging evidence suggests that GLP1R signaling influences embryonic and adult stem cell populations by regulating proliferation, survival, differentiation, and stemness, with potential implications for tissue regeneration and aging. At the same time, concerns remain regarding long-term effects on progenitor cell homeostasis, lean tissue maintenance, and reproductive health. Because most available data derive from heterogeneous preclinical studies, it remains unclear whether reported findings reflect indirect metabolic and immune effects and if they translate into meaningful clinical outcomes. This editorial highlights the growing intersection of GLP1 biology and regenerative medicine, discusses current evidence and unresolved questions, and emphasizes the need for mechanistic and clinical studies to define the impact of GLP1RAs on stem cell function and tissue regeneration.

Aging‐associated changes in myeloid cells are incompletely understood. One of the culprits of aging is the downregulation of the Tert gene coding for the catalytic subunit of telomerase. Studies of mouse models with Tert knockout (KO) in specific cells have revealed the importance of the telomere‐independent noncanonical function of TERT in supporting mitochondrial metabolism and protection from cell senescence. To investigate the role of TERT in myeloid cells (MCs), we analyzed mice with Tert KO in the LysM+ lineage, indelibly labeled with membrane green fluorescent protein (mG). Macrophage numbers and properties in various organs were compared. Changes in the vasculature, adipose tissue (AT) depots, lungs, heart, and other tissues were assessed. MC‐ Tert‐ KO mice displayed MC depletion in the bone marrow and abnormal frequencies in other organs. Tert‐ KO MCs were found to express senescence markers despite having a normal telomere length. Tert ‐KO macrophages were found to be polarized toward the pro‐inflammatory M1 phenotype, upregulate expression of genes promoting lipid uptake and retention, and be prone to conversion into foam cells. MC‐ Tert‐ KO mice fed a high‐calorie diet had increased adiposity and dysfunctional glucose metabolism. On an atherogenic diet, MC‐ Tert‐ KO mice displayed abnormal lipid metabolism and chronic fever. Aged MC‐ Tert‐ KO mice developed pulmonary fibrosis and an imbalance in right/left ventricle cardiac output. Our results show that the increased conversion of Tert ‐KO MCs into foam cells leads to systemic organ dysfunction. We conclude that TERT plays an important noncanonical function in MCs that prevents the development of aging‐associated diseases.

Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited effective disease-modifying therapies. SSc is characterized by dermal fibrosis accompanied by loss of dermal white adipose tissue (DWAT), yet the mechanisms linking adipocyte depletion to fibroblast activation remain unclear. Here we identify the transcription factor SIX1 as a central regulator coupling adipogenic repression with profibrotic signaling. SIX1 expression was increased in skin biopsies from 2 independent SSc cohorts and localized to fibroblast and perivascular stromal cells. In mice, ubiquitous or adipocyte-specific deletion of Six1 preserved DWAT, reduced collagen accumulation, and selectively decreased profibrotic mediators. In cultured fibroblasts, CRISPR/Cas9-mediated Six1 loss enhanced adipogenic markers while reducing profibrotic mediators and directly suppressed PAI-1 ( SERPINE1 ) promoter activity. Together, these data position SIX1 as a transcriptional switch that promotes adipocyte reprogramming and fibrotic progression, and they highlight SIX1 inhibition as a potential therapeutic strategy to preserve adipocyte identity and limit dermal fibrosis.

Background/objectives: Progression of pancreatic ductal adenocarcinoma (PDAC) and other carcinomas relies on cancer-associated fibroblasts (CAFs). A subset of CAFs is derived from adipose stromal cells (ASCs) recruited by tumors and the ASC-CAF conversion has been associated with invasiveness and poor prognosis. Methods: To explore the underlying molecular mechanisms, we used a model based on primary ASCs derived from human visceral adipose tissue co-cultured with human PDAC cell line Capan-1. To investigate cancer progression in vivo, we also used mice orthotopically grafted with mouse KPC cells. Results: Genomic analysis revealed that Capan-1 co-culture induces Wnt and TGFβ signaling and extracellular matrix (ECM) gene expression in ASC. We investigated the function of two markers of the fibroblastic transition highly induced by cancer cells: a long non-coding RNA LINC01614 and a Wnt signaling modulator SFRP4. By using ASCs with either SFRP4 or LINC01614 knocked out (ko), we showed that both genes are required for Wnt/TGFβ signaling and ECM induction in ASCs by Capan-1. Analysis of changes in Capan-1 genes that rely on LINC01614 and SFRP4 expression in ASCs also identified the Wnt and TGF pathways. SFRP4 ko in ASCs suppressed both migration and invasion of Capan-1 cells. We show that tumors in SFRP4 ko mice have less desmoplasia, less epithelial dedifferentiation, reduced growth rate, and reduced progression to metastasis. Conclusions: We conclude that SFRP4 promotes cancer progression in pancreatic cancer and is a promising therapeutic target.

Adipose stromal cells (ASCs) are perivascular mesenchymal progenitors of adipose tissue. In cancer patients, ASCs can mobilize and migrate to the tumor, where they subsequently play an important role in cancer progression. This biological process involves the conversion of recruited ASCs into cancer-associated fibroblasts (CAFs). ASC-derived CAFs influence the tumor microenvironment through extracellular matrix remodeling, vascularization, and immunomodulation. These and other processes mediated by secreted paracrine factors also affect gene expression in carcinoma cells to promote the epithelial-mesenchymal transition (EMT), metabolic adaptation, survival, and invasiveness of cancer cells. ASC-derived CAFs can enhance tumor aggressiveness, accounting in part for the link between obesity and mortality observed in many cancer types that are surrounded by adipose tissue. In this review, we highlight recent findings on the characteristics and functions of ASCs in cancer and discuss their potential as therapeutic targets.

We have previously reported a cyclic peptide CRAGVGRGC (termed BLMP6) that homes to disseminating tumor cells in mouse cancer models and could be used for metastasis detection and intervention. Here, based on BLMP6 similarity to latent transforming growth factor beta binding protein 4 (LTBP4), we discovered fibulin-4 as a BLMP6 target. We show that BLMP6 mimics the LTBP4 domain binding to fibulin-4 and selectively binds to fibulin-4 in vitro. Fibulin-4 knockout in mouse 4T1 cancer cells abrogated BLMP6 homing to lung metastases. Fibulin-4 expression was found to be increased in invasive and metastatic human breast cancer. AZDye555 fluorophore-labeled BLMP6 was developed as a reagent selectively binding to invasive and metastatic human breast cancer cells in tissue sections and homing to MDA-MB-231 metastases in mice. We show that radiolabeling BLMP6 with ⁶⁸ Ga can be used for the detection of MDA-MB-231 metastases. We designed a peptide-drug conjugate consisting of monomethyl auristatin E (MMAE) and BLMP6 that preferentially kills aggressive cancer cells. Cytotoxicity of MMAE-BLMP6 against MDA-MB-231 tumors was confirmed in vivo . In an immunocompetent mouse model of B16F10 experimental lung metastases, treatment with MMAE-BLMP6 suppressed metastasis growth and improved survival. There was also a trend for metastasis suppression and survival improvement in the MDA-MB-231 experimental metastasis model. Our results suggest that fibulin-4 and BLMP6 may be further developed for the detection and targeting of metastatic human cancers. Statement of significance: This study identifies fibulin-4 as a protein highly expressed in breast cancer metastasis. It evaluates the application of peptide conjugates targeting fibulin-4 in mouse models as non-invasive probes for metastasis detection and cytotoxic drug delivery.

The effects of cell senescence in individual cell populations of the tumor microenvironment (TME) on cancer progression remain unclear. Here, we investigated the effects of cell senescence caused by inactivation of the catalytic subunit of telomerase (Tert) in distinct TME components. We generated genetic Tert knockout (KO) mice driven by the LysM promoter in myeloid cells, by the Pdgfra or Pdgfrb promoter in mesenchymal cells, and by the Tie2e promoter in endothelial cells. We compared the effect of the Tert KOs in syngeneic models of orthotopically grafted E0771 breast adenocarcinoma, RM1 prostate adenocarcinoma, and KPC pancreatic adenocarcinoma. Tumors in LysM-Tert-KO, Pdgfra-Tert-KO, and Pdgfrb-Tert-KO mice displayed increased myofibrogenesis and desmoplasia. Tumors in Tie2e-Tert-KO mice displayed endothelial abnormality and the strongest reduction in tumor vascularization. This was linked with increased HIF1a protein nuclear localization, indicative of hypoxia, and the highest protein expression of the glycolytic marker GLUT1 in cancer cells. KPC tumors displayed reduced epithelial cytokeratin-19 protein expression and reduced tumor growth in all Tert KO models. However, liver metastases of KPC cells were only observed for Tie2e-Tert-KO mice. We conclude that senescence of distinct cells in the TME has different effects on cancer progression and that endothelial cell function preservation is important in metastasis suppression.

A, Fig. 4 schematic testing if D-CAN synergizes with immune checkpoint blockade (aPDL1) in male and female mice. B, Initial body weights in experimental mice. C, Tumor weight from an experiment in female mice investigating the effects of D-CAN / aPDL1 with non-immune IgG and IgG + D-CAN data combined with Fig. 4B and 4D data. *=p<0.05, **=p<0.001, ***=p<0.0001. D, Metastatic liver tumor colony assay from mice in C.