Advances in Metastatic Cancer Signaling Research

Stanford scientists have discovered that cancer cells don’t just use one trick to hide from the immune system—they use two separate “don’t-eat-me” signals to stop macrophages from killing them. The first signal, CD47, was already famous for acting like an invisibility cloak that tells macrophages to back off, and blocking it with an anti-CD47 antibody is already in human trials. In the Nature Immunology paper, the same Stanford team also found that tumors use MHC class I as a second stop signal by binding to a macrophage receptor called LILRB1, which suppresses the macrophage’s ability to engulf and destroy the cancer. When researchers blocked both CD47 and LILRB1 in mice, tumors rapidly filled with immune cells, shrank significantly, and became far easier for the body to clear. This shows that many cancers survive by running two overlapping escape systems, and turning off both “don’t-eat-me” pathways at once may dramatically boost the immune system’s ability to attack and eliminate tumors.

💫 We are thrilled to share the first hard-core immunology paper from the Batlle Lab, now published in Nature Genetics!  Very proud of the team and efforts behind it. The study was led by Ana Henriques, Maria Salvany Celades, and Alejandro Prados, in my lab, in collaboration with many outstanding colleagues at IRB Barcelona and Paula Nieto and Holger Heyn at Centro Nacional de Análisis Genómico (CNAG). ➡️ Together we unravel how TGF-β signaling builds a dual immune barrier in colorectal cancer metastases. Kudos to all 👏 🙌 🔝 We had previously shown (Tauriello et al, Nature 2018) that blocking TGF-β synergizes with immunotherapy to eradicate colorectal cancer metastases. In this new work, we dove into the immunology of metastatic disease to understand why this happens. 💡 Key findings: ✅        TGF-β acts directly on T cells, preventing the recruitment of peripheral memory CD8⁺ T cells into liver metastases. ✅         Inhibition of TGF-β signaling restores both T cell infiltration and clonal expansion, converting resistant tumors into responders to anti–PD-L1 therapy. ✅        Clonal expansion is inhibited indirectly through reprogramming of tumor-associated macrophages to express SPP1 (osteopontin), which shapes a fibrotic and immunosuppressive niche. ✅        The SPP1-driven environment prevents infiltrated T cells from proliferating, effectively. ✅         In the absence of osteopontin, immune checkpoint blockade efficacy is increased. ✅       anti–PD-L1 therapy boosted T cell motility allowing infiltrated cells to move and engage targets. Together, these findings reveal how TGF-β orchestrates immune evasion across both innate and adaptive immune compartments — and point to new strategies to improve immunotherapy outcomes in colorectal cancer. 👉 Read the full article: Henriques et al., Nature Genetics (2025) “TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1 macrophages.” https://lnkd.in/dzZmqi_c WE thank all funding agencies: This research was supported by the European Research Council (ERC), Asociación Española Contra el Cáncer, Fundación ”la Caixa”, Worldwide Cancer Research, La Marató de TV3 3Cat Corporatiu CIBERONC, AGAUR, Fundación Olga Torres, and the Spanish Ministerio de Ciencia, Innovación y Universidades . #ColorectalCancer #Immunotherapy #TGFbeta #CancerResearch #NatureGenetics #IRBBarcelona #CNAG #TranslationalResearch #IRBBarcelona

A team led by Prof Vicky Sanz Moreno (formerly of King's College London) at The Institute of Cancer Research, London, in collaboration with Barts Cancer Institute (Queen Mary University of London) discovered how #cancercells navigate the extracellular matrix (ECM) to break free from #tumors. The ECM, which acts as a scaffold for tumors, is structured differently across the tumor, influencing cancer cell mobility. 🔸 At the tumor’s center, ECM fibers are disorganized, while at the border, they are dense and aligned outward, providing a path for cancer cells to migrate. This ECM structure triggers shape changes in cancer cells, making them more invasive and capable of traveling to other organs. 🔸 The study examined tumor samples from 99 patients with #melanoma and #breastcancer, revealing that cancer cells at the tumor’s edge had higher expression of genes linked to migration, #inflammation, and ECM remodeling. These aggressive cancer cells corrupt their environment, producing enzymes such as lysyl oxidase (LOX) that restructure the ECM to facilitate their escape. Researchers found that patients with high levels of these genes had shorter survival times across 14 different cancer types, including #pancreaticcancer, #lungcancer, and #glioblastoma (#braincancer). The study highlights that these molecular markers can help identify aggressive tumors earlier and tailor treatment accordingly. 🔸 Based on these findings, scientists are now developing drugs to block the ECM’s influence on cancer cell movement. The ICR has previously researched LOX inhibitors, and these drugs, currently in clinical trials, could prevent cancer cells from escaping by stabilizing the ECM. The study suggests that disrupting the ECM’s fiber network could also help improve drug delivery, making tumors more receptive to treatment. 🔸 Future research will explore how targeting ECM fiber density could not only prevent metastasis but also enhance the effectiveness of existing cancer therapies. This decade-long research, published in Nature Communications, paves the way for proactive #cancertreatment strategies, shifting focus from managing metastatic disease to preventing its spread at an earlier stage. 📑 More information: Oscar Maiques, Marta Sallan, Roman Laddach, et al, Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis, Nature Communications (2025). https://lnkd.in/eXz5EKme

#ScienceSaturday ❓ Why do some cancer cells survive the immune system’s attack when they first spread to new organs? ➡️ A new study in Nature Portfolio shows metastatic #cancer cells can exploit stress-hormone signaling to evade immune destruction. Researchers found that activation of the glucocorticoid receptor (GR) helps tumor cells resist killing by T cells and natural killer cells during the earliest stages of metastasis. ➡️ GR signaling suppresses the FAS–FASL pathway, one of the key ways immune cells trigger cancer-cell death. ➡️ When researchers blocked GR signaling and combined it with #immunotherapy in vivo, metastatic tumors were reduced and survival improved. 🌟 The takeaway: Immune escape may begin very early in metastasis. Targeting stress-hormone signaling alongside immunotherapy could help eliminate metastatic “seeds” before new tumors take hold. 🔗 Read more in Nature: https://lnkd.in/ex_6knjj Dana-Farber Cancer Institute Harvard Medical School

Metastatic breast cancer remains largely incurable, with survival rates dropping from over 90% for localized disease to around 25% for distant metastases. Understanding how the tumor microenvironment changes during this transition is critical for developing better treatments. Recent research from Oregon Health & Science University provides new insights into these cellular transformations. Methods: Researchers analyzed single-cell RNA sequencing data from 23 female patients with estrogen receptor-positive (ER+) breast cancer—12 with primary tumors and 11 with metastases across multiple sites including liver, bone, lymph nodes, and skin. This comprehensive approach examined nearly 100,000 individual cells to understand how different cell types behave in primary versus metastatic settings. Results: The study revealed several key differences between primary and metastatic tumors: - Immune System Changes: Metastatic tumors showed a shift toward immunosuppression, with increased numbers of exhausted T cells and regulatory T cells that dampen immune responses. Primary tumors maintained more pro-inflammatory immune cell populations. - Macrophage Polarization: Primary tumors contained more immune-activating macrophages (FOLR2+ and CXCR3+), while metastatic sites were dominated by tumor-promoting macrophages expressing CCL2, SPP1, and MMP9—proteins associated with invasion and immune suppression. - Metabolic Reprogramming: T cells in primary tumors relied on glycolysis for energy, supporting rapid immune responses. In metastatic sites, T cells shifted to fatty acid metabolism and oxidative phosphorylation, potentially contributing to immune exhaustion. - Stromal Remodeling: Cancer-associated fibroblasts changed from inflammatory and antigen-presenting types in primary tumors to matrix-remodeling types in metastases, creating an environment that supports tumor growth and blocks immune infiltration. - Cellular Communication: The study identified a marked decrease in communication between tumor cells and immune cells in metastatic tissues, contributing to immune evasion. Conclusions: This research demonstrates that metastatic progression involves coordinated changes across multiple cell types, not just cancer cells themselves. The tumor microenvironment becomes increasingly immunosuppressive through specific cellular reprogramming events. These findings suggest potential therapeutic targets, including the TNF-α/NF-κB pathway that was more active in primary tumors, and specific macrophage subtypes that could be targeted to restore immune function in metastatic disease. Paper and research by @Furkan Ozmen and larger team

Weill Cornell Medicine may have just cracked TNBC’s deadliest secret: metastasis. - Triple-negative breast cancer (TNBC) kills mostly through spread, not primary tumors. - Researchers tied metastasis to an epigenetic enzyme, EZH2, which destabilizes chromosomes during cell division. - Blocking EZH2 with tazemetostat restored order - and cut metastasis in preclinical models. - First time an epigenetic regulator has been directly linked to chromosomal stability in cancer. Why this matters: For decades, the playbook was to push tumors into more instability. This flips the script. Stabilizing chromosomes may actually halt spread - the single biggest driver of TNBC deaths. Who should care: Oncologists eyeing new strategies, biotech teams repurposing EZH2 inhibitors, and investors looking at metastasis-blocking drugs as a new class. If this translates to the clinic, it’s not just another breast cancer therapy. It’s the beginning of precision anti-metastatic medicine.

In vivo screening of the CRISPR genome identifies the transcriptional modulator CITED2 as an essential factor in the progression of prostate cancer to bone metastases. The discovery not only improves understanding of the molecular basis of the disease, but also opens up new avenues for targeted therapies, potentially revolutionizing treatment paradigms for patients battling advanced prostate cancer. The study meticulously engineered non-metastatic human prostate cancer cell lines to activate or inhibit gene expression using CRISPRa or CRISPRi technology. Modified cancer cells were then implanted into the prostate of nude mice, and following tumor development and emergence of metastases, primary and metastatic tumors were harvested for analysis. In vivo CRISPR screening identified CITED2 as an important promoter of bone metastasis, standing out among various genes for its substantial impact. Subsequent functional validation experiments, including innovative organ-on-a-chip assays, reinforced CITED2's role in promoting bone invasion, highlighting its potential as a therapeutic target. The research also looked at CITED2-driven transcriptional profiles, revealing distinct patterns of primary and metastatic cancer, which could inform the development of precision medicine approaches. 

🔬 Unlocking the Potential of the Tumor Microenvironment (TME) 🔎 💡 Cancer remains a formidable global health challenge, with metastasis responsible for most cancer-related deaths. A recent review in the Journal of Hematology & Oncology highlights the intricate role of the TME in shaping cancer progression, therapeutic resistance, and treatment innovation. Here are the key takeaways from this groundbreaking research 👇: 🔬 Decoding the Tumor Microenvironment (TME): A Complex Ecosystem The TME isn’t just a backdrop—it actively orchestrates cancer progression. It comprises: 🔹 Cancer-Associated Fibroblasts (CAFs): The most abundant stromal cells in tumors. These cells remodel the extracellular matrix (ECM), secrete cytokines like TGF-β, and drive processes like Epithelial-Mesenchymal Transition (EMT), which enhances cancer invasiveness and therapy resistance. 🔹 Immune Cells: ▪️ TAMs (Tumor-Associated Macrophages): Modulate immune suppression and support metastasis. ▪️ TANs (Tumor-Associated Neutrophils): Trigger EMT and secrete IL-17A, activating JAK2/STAT3 signaling to boost migration and invasion. ▪️ Natural Killer (NK) Cells: These innate immune cells directly attack tumors but can be influenced by the TME to suppress their activity. 🔹 Extracellular Matrix (ECM): Provides structural support but also facilitates EMT through matrix stiffness and signaling pathways like YAP/TAZ activation. 💡 Innovative Therapeutic Strategies 🧬 Targeting EMT: 🔹 Key signaling molecules like TGF-β, Wnt/β-catenin, and HIF-1α are major drivers of EMT. Strategies that inhibit these pathways could disrupt metastasis. 🔹 Hypoxia-Driven EMT: Tumor hypoxia stabilizes HIF-1α, upregulates Snail and Twist, and promotes invasion. 🛠️ Disrupting the TME’s Support System: ❌ Blocking CAF activity: Targeting secreted factors like IL-6, TGF-β, and periostin has shown promise in pre-clinical models. ✔️ Modulating immune responses: Inhibitors targeting immune checkpoints and cytokine signaling (e.g., IL-6/TGF-β crosstalk) can re-activate anti-tumor immunity. ✨ Emerging Insights: 1️⃣ 3D Models of TME: New biomimetic culture systems mimic ECM properties, offering better platforms for testing drugs. 2️⃣ Dual Roles of TME Components: Molecules like TGF-β act as tumor suppressors in early cancer stages but drive metastasis later, underscoring the need for context-specific interventions. 3️⃣ Therapeutic Resistance: EMT confers stem-like properties to cancer cells, enhancing drug resistance and promoting relapse. 📊 Key Findings 🔹 Matrix Stiffness: Increased ECM rigidity drives EMT by activating YAP/TAZ and downstream pathways like TWIST1 and Snail. 🔹 CAFs and Growth Factors: CAF-derived HGF, EGF, and FGF-2 promote EMT and metastasis. 🔹 Immune Suppression: MDSCs and Tregs within the TME inhibit T-cell activity, allowing cancer cells to evade immune surveillance. #CancerResearch #TumorMicroenvironment #OncologyInnovation #EMT #Immunotherapy

New visualization tool targets breast cancer dissemination. Cancer cell movement during metastasis is a dynamic process regulated by several different signals. The way cells receive, process and respond to signals has been hard to detect. A new study led by Professor Johanna Ivaska and Dr James Conway, researchers at the University of Turku, have developed a fluorescent probe to visualize signaling dynamics in moving cancer cells, a new therapeutic possibility for limiting breast cancer spread. Finland. 02 June 2025 Excerpt: “Signaling networks inside cells control everything from growth to movement, but visualizing in living cells requires new and refined methods," explained Dr James Conway, lead researcher. “I set out to see these invisible signals and came up with a new tool, which we call Illusia, to do just that.” Breast cancer patients who experience transition from pre-malignant ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) face a poorer prognosis and metastatic disease is incurable. Note: The research team's work focuses on identifying factors that regulate metastatic movement of breast cancer cells, with protein phosphatase Shp2, “Ship two”, emerging as a key regulator of metastasis through regulation of cancer cell interactions with surrounding tissue. Note: “Cell movement is essential for cancer cells to spread from the primary tumor to secondary sites. Even though widely recognized as the key step in cancer progression, there are currently no cancer therapies that block cell migration or invasion. Our research finds drugs currently in clinical trials for blocking growth in other tumor types may also be effective in blocking breast cancer spread,” says Professor Johanna Ivaska, the Principal Investigator on the project. The implications of this discovery extend beyond breast cancer alone and may help us to understand cancer cell invasion from solid tumors more generally. "Researchers developed color-based probes to detect different events in live cells, but this type of cell-dynamics reporter had not been available before. It has transformed our understanding of signaling needed for cell movement,” explained Dr Conway, continuing, “These probes often acquire names from pop culture references. The lab came up with the name Illusia, drawing from an old Finnish story about a fairy that comes to earth from the rainbow. This gave our work a colorful twist, we are all seeking in today’s world, as we strive for better treatments.” The team is now exploring therapeutic avenues that have opened up as a result of the recent findings. Online link to the research article published 26 May 2025 in Nature Cell Biology enclosed.