bims-ecemfi 2026-05-17 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–05–17
seven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Tuning scaffold degradation with non-natural peptidomimetics to control human umbilical vein endothelial cell morphology and vessel formation.
Dual-Responsive Hydrogels Engineer Anisotropic Cellular Microenvironment to Modulate Stem Cell Organization and Fate.
Local Tumor Microenvironment Niches Correlate With Survival And Immunotherapy Response In Human Glioblastoma.
E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer.
Tumor cell-derived HSP47 promotes pancreatic Cancer metastasis via Homotrimeric collagen-mediated M2 macrophage polarization.
Cell rearrangement progression along the apical-basal axis is linked with 3D epithelial tissue structure.
Targeting the αvβ5 Integrin Modifies the TGF-β-Rich Tumor Microenvironment of Pancreatic Cancer.

Acta Biomater. 2026 May 08. pii: S1742-7061(26)00296-5. [Epub ahead of print]

Tuning scaffold degradation with non-natural peptidomimetics to control human umbilical vein endothelial cell morphology and vessel formation.

Kathleen N Halwachs, Carolyn M Watkins, Morgan J Valdivieso, Janet Zoldan, Adrianne M Rosales.

  The vascularization of 3D tissue constructs, such as hydrogels, remains a paramount challenge in tissue engineering. Extracellular matrix degradation and remodeling are key parts of the vascularization process; however, it is difficult to isolate the effects of degradability in both natural and synthetic matrix models. Naturally-derived matrices typically couple degradability to other material properties, whereas synthetic matrices rely on short peptide sequences to impart degradability, which may exhibit substrate overlap to many proteases and confound degradability trends in vivo. Here, we present a method to systematically tune 3D hydrogel degradation across multiple proteases using crosslinkers with non-natural peptoid (N-substituted glycine) substitutions. Increased peptoid substitutions reduced hydrogel degradability to proteases without altering hydrogel modulus, swelling ratio, or crosslinker length. Using this approach, human umbilical vein endothelial cells (HUVECs) encapsulated in more degradable hydrogels proliferated more, formed more vessels, exhibited higher metabolic activity, and secreted more extracellular matrix than HUVECs encapsulated in less degradable or non-degradable hydrogels. Interestingly, HUVECs encapsulated in the least degradable hydrogels secreted significantly higher matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) than HUVECs encapsulated in the most degradable hydrogels, suggesting higher MMP secretion to compensate for the reduced matrix degradability. Overall, this work highlights the importance of protease-mediated remodeling on vascularization and suggests that peptoid substitutions are effective for tuning hydrogel degradability for a variety of 3D cell applications. STATEMENT OF SIGNIFICANCE: Vascularization of 3D tissue constructs relies on scaffold degradability to accommodate matrix remodeling. Many strategies for proteolytic degradability have been developed; however, these strategies typically couple degradability to other material properties or do not predictably decrease degradation to a complex protease profile. This work presents a strategy to tune hydrogel degradability using peptide crosslinkers with non-natural peptoid substitutions. Increased peptoid substitutions decrease hydrogel proteolytic degradability without altering chemical composition, crosslinker length, or other material properties of the scaffold. The degradability of the developed hydrogels significantly impacted human umbilical vein endothelial cell vessel formation, metabolic activity, morphology, and protease secretion, indicating this strategy is effective for decoupling degradability from other scaffold properties for a variety of biological applications.

Keywords:  Degradability; Hydrogel; Peptidomimetics; Vascularization

DOI:  https://doi.org/10.1016/j.actbio.2026.05.013
Small. 2026 May 14. e00072

Dual-Responsive Hydrogels Engineer Anisotropic Cellular Microenvironment to Modulate Stem Cell Organization and Fate.

Hongjuan Weng, Wen Chen, Lei He, Timo Rademakers, Sabine van Rijt, Monize C Decarli, Katrien V Bernaerts, Lorenzo Moroni.

  Biophysical and biochemical cues in the local cellular microenvironment, including topography, matrix mechanics, and growth factors, significantly regulate stem cell fate. However, strategies for in vitro replicating such complex organized three-dimensional (3D) cellular microenvironments and modulating cell alignment and differentiation by these cues in cell-laden hydrogels are far less developed. This study introduces light-responsive collagen peptide hydrogels mixed with magnetic nanoparticles as physical crosslinkers, leading to in situ formation of an organized network of human bone marrow mesenchymal stem cells (hMSCs) under magnetic-driven anisotropy. Moreover, by simply tailoring the nanoparticle surface with dopamine methacrylamide, chemical nanoparticle crosslinkers with dual magnetic-light-responsiveness are developed to tune matrix mechanical dynamics without significantly changing hydrogel stiffness and components. The encapsulated hMSCs exhibit enhanced spreading, alignment, and differentiation into ligamentocytes/tenocytes in anisotropic hydrogels with faster mechanical dynamics and transforming growth factor beta-3, contributing to the synergistic effects of these biophysical and biochemical cues. These simple manufacturing and conditioning strategies, which directly incorporate stimuli-responsive nanoparticle crosslinkers into cell-laden hydrogels, show great potential in developing advanced 3D organized in vitro models to modulate stem cell organization and fate.

Keywords:  anisotropic hydrogels; biochemical cues; biomechanical cues; biophysical anisotropic cues; cell alignment; magnetic nanoparticles

DOI:  https://doi.org/10.1002/smll.202600072
bioRxiv. 2026 Feb 23. pii: 2026.02.23.707276. [Epub ahead of print]

Local Tumor Microenvironment Niches Correlate With Survival And Immunotherapy Response In Human Glioblastoma.

Florent Petitprez, Sheila Webb, Gillian Morrison, Lorenzo Merotto, Jessica Webb, Yuxuan Xie, Ekin Guney, William A Weiss, Francesca Finotello, Takanori Kitamura, Steven M Pollard, Jeffrey W Pollard.

Background: Glioblastoma (GBM) is an aggressive form of primary brain cancer. Recent efforts to characterize GBM using single-cell or spatially-resolved transcriptomics have revealed a tremendous intra-tumoral heterogeneity between malignant cells and between different tumor areas. However, most efforts have focused on malignant cells, and the spatial and cellular heterogeneity of the tumor microenvironment (TME) remains poorly understood. Moreover, it is unclear how TME compositions and organizations influence clinical outcomes for patients.
Results: Integrating spatial transcriptomics, single-cell RNA-seq and histology on 25 tumors, cellular composition of the TME was estimated on over 46,000 55-μm wide spots. Spatial associations were revealed between mesenchymal-like cancer cells and monocyte-derived macrophages. Spots were clustered into six unique classes of TME, exhibiting differential composition of malignant and immune cells, and distinct activation of biological pathways. Spatial transcriptomics-informed deconvolution of large-scale bulk RNA-seq datasets revealed that the niche composition of tumors associated significantly with patient survival and response to immunotherapy. Mesenchymal-like, monocyte-derived macrophages-rich and hypoxic niche N1 associated with lower overall survival while oligodendrogial progenitor-like and microglia-derived macrophages-enriched niche N5 is associated with longer patients' survival. Analysis of data from patients treated with immunotherapy showed that niches N1 and mixed mesenchymal-like and astrocyte-like niche N3 associated with response to PD-1 inhibitors.
Conclusions: Our results show that GBM exhibits a strong spatial heterogeneity of TMEs, with distinct categories of niche. The niche composition of tumors associated with survival and immunotherapy response. Our results suggest incorporation of TME niches as biomarkers for risk stratification and therapeutic decisions for patients.

DOI: https://doi.org/10.64898/2026.02.23.707276
Nat Commun. 2026 May 12.

E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular breast cancer.

Lounes Djerroudi, Rana Mhaidly, Yann Kieffer, Isabelle Damei, Hugo Croizer, Vithuzane Selvarasa, Geraldine Gentric, Laetitia Fuhrmann, Andreia Goncalves, Martial Caly, Camille Richardot, Renaud Leclere, Enora Laas, Caroline Malhaire, Kim Cao, Julia M Houthuijzen, Pim Kloosterman, Jos Jonkers, Camille Benoist, Victor Renault, François-Clément Bidard, Anne Vincent-Salomon, Fatima Mechta-Grigoriou.

Invasive lobular breast carcinoma (ILC) shows specific stromal features, and a high tumor-infiltrating lymphocyte (TIL) content being associated with poor patient prognosis. Here, we reveal the underlying mechanism by performing single-cell analysis, immunohistochemistry, deconvolution of bulk RNA-sequencing in a large female ILC series and functional assays. We show that E-cadherin (CDH1)-loss in breast cancer cells prevents differentiation of FAP+ inflammatory cancer-associated fibroblasts (iCAF) into FAP+ myofibroblastic CAF, leading to iCAF accumulation in ILC. In turn, FAP+ iCAF attract TILs into the tumor center, shaping their spatial organization. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape through a lack of retention and activation of ITGAE-expressing resident memory CD8 + T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, FAP+ iCAF and CD8 + TRM, providing insights into the ILC stromal reaction and revealing why and how TILs are associated with poor prognosis in ILC patients, a mechanism generalizable to other CDH1-inactivated cancer types.

DOI: https://doi.org/10.1038/s41467-026-72844-4
Cell Signal. 2026 May 12. pii: S0898-6568(26)00242-1. [Epub ahead of print] 112589

Tumor cell-derived HSP47 promotes pancreatic Cancer metastasis via Homotrimeric collagen-mediated M2 macrophage polarization.

Xinxin Ling, Yaqin Zhang, Le Zhu, Zijin Xu, Yufang Bao, Hanchao Lin, Jiajun Wu, Jiong Shi, Liang Liu, Qiongzhu Dong.

  The metastatic progression of pancreatic ductal adenocarcinoma (PDAC) is governed by dynamic interactions between cancer cells and immune cells within the tumor microenvironment; yet the underlying mechanisms remain largely elusive. Here, single-cell analysis identifies the collagen-specific chaperone HSP47 as predominantly expressed in PDAC epithelial cells. High HSP47 expression drives liver metastasis and serves as a predictor of poor survival in PDAC patients. Mechanistically, tumor cell-derived HSP47 promotes PDAC metastasis by creating an immunosuppressive microenvironment. It drives the secretion of a homotrimeric, tumor-specific form of collagen I (α1/α1/α1, also referred to as COL1) into the extracellular matrix (ECM) (rather than modulating its protein expression), which is essential for HSP47-mediated immunosuppression in PDAC. The accumulated COL1 polarizes tumor-associated macrophages (TAMs) toward an immunosuppressive M2 phenotype via the integrin α2β1/MAPK/ERK signaling pathway. These reprogrammed M2 macrophages, in turn, establish a feedforward loop by enhancing epithelial-mesenchymal transition (EMT) in PDAC cells through macrophage-derived Phosphoglycerate mutase 1 (PGAM1) in an ACTG1-dependent manner (Actin Gamma 1, ACTG1). In summary, our findings highlight the critical role of the HSP47-COL1-PGAM1 axis in PDAC metastasis, unveiling a previously unrecognized pro-metastatic regulatory circuit that provides mechanistic insights into PDAC progression.

Keywords:  HSP47; M2 macrophage polarization; Metastasis; PDAC; PGAM1

DOI:  https://doi.org/10.1016/j.cellsig.2026.112589
PRX Life. 2026 Mar;pii: 013005. [Epub ahead of print]4(1):

Cell rearrangement progression along the apical-basal axis is linked with 3D epithelial tissue structure.

Erika M Kusaka, Sassan Ostvar, Xiaoyun Liu, Xun Wang, Tianyi Liu, Karen E Kasza.

  Epithelial tissues undergo extensive structural remodeling during embryonic development. Tissue remodeling is often enabled by oriented cell rearrangements that are linked with patterns of mechanical stresses in the tissue and with tissue mechanical properties. Cell rearrangements and their links to tissue structure have largely been studied at the apical side of tissues at the level of adherens junctions. Less is known about the involvement of basolateral domains in cell rearrangements. Here we use live confocal imaging to quantify cell rearrangements, cell packing structure, and cell morphology in 3D in the converging and extending Drosophila germband epithelium. We report gradients in cell shapes and tissue structure along the apical-basal axis of the germband, suggesting that the apical and basolateral domains display distinct behaviors. Cell rearrangements initiate at apical as well as basolateral positions, with initiation frequencies also displaying a gradient along the apical-basal axis. Analyses of cell contact angles and non-muscle myosin II localization patterns during cell rearrangements indicate that rearrangements can be actively driven in lateral as well as in apical regions of the tissue. Following initiation, rearrangements propagate across the apical-basal axis and lateral cell contacts remodel; these events involve scutoids and other complex 3D cell shapes as intermediate states. These findings uncover novel aspects of the cell rearrangements that drive dynamic remodeling of epithelia and reveal links between rearrangements and gradients in tissue structure along the apical-basal axis.

Keywords:  Drosophila; apical-basal polarity; convergent extension; epithelial morphogenesis; germband extension; tissue remodeling

DOI:  https://doi.org/10.1103/l5r5-pb9t
Cancer Res. 2026 May 14.

Targeting the αvβ5 Integrin Modifies the TGF-β-Rich Tumor Microenvironment of Pancreatic Cancer.

Kodai Suzuki, Yuki Kunisada, Yukihito Kuroda, Hotaka Kawai, Tatiana Hurtado de Mendoza, Evangeline S Mose, Shingo Eikawa, Henri Havia, Tero A H Järvinen, Caisheng Lu, Erkki Ruoslahti, Andrew M Lowy, Norio Miyamura, Kazuki N Sugahara.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its aggressive, therapy-resistant nature that is in part driven by the desmoplastic, hypo-perfused, and immunosuppressive tumor microenvironment (TME). Here, we demonstrated that the αv integrin- and neuropilin-1 (NRP-1)-dual targeting iRGD peptide reverses some of these TME features by inhibiting transforming growth factor-β (TGF-β) activation in the tumor, a process mediated by the αvβ5 integrin. In addition to PDAC epithelial cells and fibroblasts, regulatory T cells (Tregs) in PDAC tumors also expressed the αvβ5 integrin and NRP-1. The αvβ5+ Tregs potently inhibited T cell proliferation, and systemic iRGD therapy not only depleted αvβ5+ Tregs from PDAC tumors but also reduced their αvβ5- counterparts. Mechanistically, iRGD inhibited the activation of TGF-β mediated by the αvβ5-rich TME, thereby depriving Tregs of the cytokine essential for their development and maintenance. NRP-1-dependent tumor penetration was required for this effect because a traditional RGD peptide without an NRP-1-binding motif failed to inhibit TGF-β signaling or deplete Tregs in vivo. Treatment with iRGD induced a series of additional TME changes, such as improved vascular patency and perfusion, reduced stromal fibers, and increased CD8+ T cell entry into the core of the tumors. Combining iRGD with immune checkpoint blockade led to an enhanced anti-tumor effect. Together, these findings support targeting the αvβ5 integrin with affinity ligands such as iRGD as a potential approach to enhance immunotherapy efficacy against PDAC and other desmoplastic tumors with high TGF-β and αvβ5 expression.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4223