Abstract 7483: Adhesion plasticity and bidirectional paracrine signaling cooperatively drive glioblastoma invasion

Cancer Research · 2026-04-03

Abstract Glioblastoma (GBM) lethality stems from diffuse invasion beyond surgical margins. EGFR amplification is frequent, and constitutively active mutant EGFRvIII co-exists with wild-type EGFR (wtEGFR) cells in ∼50% of tumors, yet cell-intrinsic and extrinsic mechanisms coupling this heterogeneity to invasion remain unresolved. Murine astrocytes engineered with wtEGFR or EGFRvIII expression were interrogated across complementary 2-D, 3-D, and in-vivo platforms. Here, we found that EGFRvIII cells were ∼40% less adherent, enabling faster migration than their wtEGFR counterparts. EGFRvIII conditioned media reduced adhesion strength of wtEGFR cells, but direct co-culture showed bidirectional signaling, with both populations experiencing a two-fold decrease in adhesion strength. Cooperative adhesion reduction was induced by a secretome unique to co-cultured cells, further suggesting bidirectional communication. Adhesion changes also cause post-“education” differences in invasion mode; EGFRvIII cells alone disseminate in a follow-the-leader mode but switch to single cell scattering when co-cultured with wtEGFR (and similar to the wt cells only condition). In addition to mode, the extent of migration is impacted by co-culture; mixed co-culture spheroids invade the matrix more extensively (>2-fold) than spheroids of either population alone, mirroring how patient tumors heterogeneity scales with invasiveness and prognosis. Moreover, RNA-seq, cytokine-arrays, and intracranially injected in vivo mouse models identified transcriptional and signaling alterations that could drive GBM adhesion. Heterotypic interaction between wtEGFR and EGFRvIII induces remodeling of focal adhesions through a distinct paracrine program, highlighting cooperative invasion. Targeting this adhesion-modulating axis offers a strategy to limit diffuse GBM spread. Together, these data show that both intrinsic and extrinsic signaling propel glioma migration and nominate new therapeutic entry points to improve patient outcomes. Citation Format: Abhinaba Banerjee, Audrey Iwashita, Afsheen Banisadr, Frank Furnari, Adam Engler, . Adhesion plasticity and bidirectional paracrine signaling cooperatively drive glioblastoma invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7483.

Stiffness-mediated paracrine signaling enhances induction of EMT in oral squamous cell carcinoma

APL Bioengineering · 2025-12-01

Oral Squamous Cell Carcinoma (OSCC) contains diverse communities of cells within the oral mucosa. A subset of the epithelia is highly responsive to changing niche conditions, resulting in their loss of polarity, epithelial-to-mesenchymal transition (EMT), and invasion in tumor-adjacent stroma. Given the range of cell states, we sought to understand how cytokine-mediated signaling from mesenchymal SCC25 cells or stiffness-induced mesenchymal (simCal27) cells caused EMT in naïve Cal27 epithelial cells. Media conditioned by SCC25 enhanced Cal27 cell migration, nuclear localization of EMT markers, and caused transcriptomic changes related to cytokine response ontological terms. SCC and simCal27 cells have unique cytokine profiles, which when regressed against transcriptomic changes, suggested that higher expression of IL-1a, IL-6, IL-8, Angiogenin, and PAI-1 in conditioned media could drive EMT; upregulation of these cytokines also appears impactful for overall survival and progression-free interval. However, depletion and supplementation assays clearly show that the presence of these specific cytokines is critical to induce a migratory phenotype and that naïve Cal27's motility is regulated by MAPK and AKT signaling pathways; loss or inhibition of these pathways reduced migration. These data suggest that paracrine signals from stiffness-induced mesenchymal cells act via distinct kinase pathways and may be necessary for cooperative dissemination of OSCC.

Applying physical principles to cancer research

APL Bioengineering · 2025-06-01

Abstract Thu144: Prolonged Cardiac Fibroblast Conditioning on Soft Matrix Maintains Quiescence but Permits Agonist-Mediated Myofibroblast Activation

Circulation Research · 2025-08-01

Cardiovascular disease continues to be the leading cause of death globally, and adverse extracellular matrix (ECM) remodeling often plays a critical role in reduced heart function during disease. Persistent activation of cardiac fibroblasts (CF) can cause them to increase ECM deposition, leading to myocardial fibrosis. While inflammatory cytokines or increased ECM stiffnesses are necessary to activate CFs, the extent to which intrinsic matrix properties activate CFs is less clear. Pluripotent stem cell-derived cardiac fibroblasts were cultured in low-serum media, serially passaged on a range of ECM stiffness, and then selectively replated on ECM of different stiffness with or without myofibroblast agonists to assess the persistence of ECM-induced activation. As classically seen with primary cells, stem-cell derived CFs cultured on tissue culture plastic for multiple passages and in the presence of myofibroblast agonists become activated myofibroblasts. However, these same CFs on soft substrates become quiescent-like but remain capable of responding to myofibroblast agonists and activating. To assess mechanical “memory” of the prior niche, CFs were cultured on tissue culture plastic and then replated to soft or stiff ECM; when the niche softened, CFs lost a-smooth muscle actin (aSMA) expression but did not when the niche remained stiff. Surprisingly, CFs on softened matrix became the most activated when exposed to myofibroblast agonists or a histone deacetylase inhibitor. These data suggested epigenetic regulation of CF mechanical “memory”, with ATAC-seq showing that softened matrix facilitates CF response to agonists via enhanced accessibility of myofibroblast transcription sites. These results highlight the need for physically relevant in vitro models that account for the epigenetic and mechanical history of CFs.

Graphene-polymer nanofibers enable optically induced electrical responses in stem cell-derived electrically excitable cells and brain organoids

Biomaterials · 2025-05-21 · 6 citations

Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer

Nature Cell Biology · 2025-09-01 · 14 citations

Abstract Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)–paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FAT L994E knock-in mouse, which disrupts FAK–paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK–paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer.

Abstract 2582: Silencing MICAL2 expression in pancreatic cancer cells rewires the tumor microenvironment through the IL1-a/p38 MAP kinase/STAT-3 axis and sensitizes tumors to immune checkpoint blockade therapy

Cancer Research · 2025-04-21

Abstract Introduction: PDAC, characterized by fibroinflammatory stroma, involves cancer cell-microenvironment interactions driving progression and resistance. ChIP-seq on resected PDAC samples identified MICAL2 as a super-enhancer-associated gene involved in tumor progression. MICAL2, a flavin monooxygenase, promotes actin depolymerization and SRF transcription. This study evaluates how MICAL2 in tumor cells affects the PDAC microenvironment via the IL1-a/p38 MAP kinase/STAT3 axis. Methods: AsPC-1 and KPC-Shcontrol (ShCNT) and MICAL2 (M2KD) cells were injected to assess tumor growth. Sc-RNA seq, immunophenotyping, immunohistochemistry, and atomic force microscopy were performed on tumors. CD8+ T cells were depleted using antibodies. CD8+ T cells from M2KD tumors were adoptively transferred via tail vein injection. Anti-PD1 and anti-IL-1α antibodies were administered IP. RNA-Seq and q-PCR were performed on ShCNT and M2KD cells. PSCs were exposed to conditioned media (CM) from cancer cells with/without MICAL2, and inflammation/fibrosis gene expression was analyzed by q-PCR. Results: Orthotopic injection of KPC-M2KD cells decreased tumor growth. Sc-RNA and immunohistochemistry showed fewer CAFs in M2KD tumors. M2KD tumors had less collagen/fibronectin deposition and reduced tissue stiffness. Increased intertumoral infiltration of cytotoxic and effector CD8+T cells was observed in M2KD tumors. CD8+T cell depletion reversed M2KD tumor growth inhibition. Adoptive transfer of CD8+T cells from M2KD tumors inhibited control tumor growth. RNA-seq revealed decreased IL1-α expression in M2KD cells. IL-1R expression on PSCs was reduced cocultured with M2KD vs. control CM. PSCs co-cultured with CM from M2KD cells showed significant downregulation of IL-6, Cxcl1, and LIF. MICAL2 regulates p38 MAP kinase phosphorylation, affecting IL1-α expression and STAT3 activation, confirmed by adding a p38 inhibitor. Immune checkpoint blockade PD-1 significantly reduced M2KD tumor size; 50% of M2KD tumor-bearing mice had complete tumor regression with PD-1 and neutralizing IL-1α antibodies. Conclusion: MICAL2 mediates tumor-stromal crosstalk via the IL1-α/p38/STAT3 axis, creating an immunosuppressive PDAC environment. MICAL2 is a potential immunomodulatory target for pancreatic cancer therapy. Citation Format: Bharti Garg, Evangeline S. Mose, Edgar Esparaze, Jay Patel, Rithika Medari, Sarah Sass, Alexei Martsinkovskiy, Asmina Courelli, Gisselle Gonzalez, Adam Engler, Parag Katira, Herve Tiriac, Andrew Lowy. Silencing MICAL2 expression in pancreatic cancer cells rewires the tumor microenvironment through the IL1-a/p38 MAP kinase/STAT-3 axis and sensitizes tumors to immune checkpoint blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2582.

ANGI-06. ADHESION PLASTICITY AND BIDIRECTIONAL PARACRINE SIGNALING COOPERATIVELY DRIVE GLIOBLASTOMA INVASION

Neuro-Oncology · 2025-11-01

Abstract Glioblastoma (GBM) lethality stems from diffuse invasion beyond surgical margins. EGFR amplification is frequent, and constitutively active mutant EGFRvIII co-exists with wild-type EGFR (wtEGFR) cells in ~50% of tumors, yet cell-intrinsic and extrinsic mechanisms coupling this heterogeneity to invasion remain unresolved. Murine astrocytes engineered with wtEGFR or EGFRvIII expression were interrogated across complementary 2-D, 3-D, and in vivo platforms. Here, we found that EGFRvIII cells were ~40% less adherent, enabling faster migration than their wtEGFR counterparts. EGFRvIII conditioned media reduced the adhesion strength of wtEGFR cells, but direct co-culture showed bidirectional signaling, with both populations experiencing a two-fold decrease in adhesion strength. Cooperative adhesion reduction was induced by a secretome unique to co-cultured cells, further suggesting bidirectional communication. Adhesion changes also cause post-“education” differences in invasion mode; EGFRvIII cells alone disseminate in a follow-the-leader mode but switch to single cell scattering when co-cultured with wtEGFR (and similar to the wt cells only condition). In addition to mode, the extent of migration is impacted by co-culture; mixed co-culture spheroids invade the matrix more extensively (>2-fold) than spheroids of either population alone, mirroring how patient tumor heterogeneity scales with invasiveness and prognosis. Moreover, RNA-seq, cytokine-arrays, and intracranially injected in vivo mouse models identified transcriptional and signaling alterations that could drive GBM adhesion. Heterotypic interaction between wtEGFR and EGFRvIII induces remodeling of focal adhesions through a distinct paracrine program, highlighting cooperative invasion. Targeting this adhesion-modulating axis offers a strategy to limit diffuse GBM spread. Together, these data show that both intrinsic and extrinsic signaling propel glioma migration and nominate new therapeutic entry points to improve patient outcomes.