Role of Cellular Functions in Cancer Development

Swedish team discovered mitochondria role in cancer proposing novel treatment approach today. Mitochondria—cellular power plants—have central but underappreciated roles in cancer development. Swedish researchers at Uppsala University discovered that cancer cells modify mitochondrial function enabling unrestricted proliferation while evading immune detection. Targeting cancer-specific mitochondrial adaptations offers novel therapeutic approach converting cancer's metabolic advantage into vulnerability. The mechanism involves cancer cells reprogram mitochondrial metabolism through mutations in mitochondrial DNA and altered metabolic enzyme expression. These changes enable rapid energy production supporting hyperproliferation while generating metabolic byproducts suppressing immune recognition. Cancer cells essentially hack mitochondrial machinery for survival advantage. This mitochondrial addiction creates opportunity: target cancer-specific metabolic dependencies. Researchers identified metabolic inhibitors specifically targeting cancer mitochondria: drugs blocking succinate dehydrogenase, blocking electron transport chain complex I, or blocking mitochondrial calcium handling. These inhibitors selectively kill cancer cells dependent on altered mitochondrial metabolism while relatively sparing normal cells with standard metabolism. Early trials treating 67 cancer patients showed 42% objective response rate—meaningful for previously treatment-resistant disease. The elegant part involves combining mitochondrial-targeting drugs with immune checkpoint inhibitors: removing mitochondrial-dependent metabolic immunosuppression allows immune systems to attack cancer simultaneously targeted at metabolic level. Dual targeting—metabolism plus immunity—overcomes compensatory mechanisms enabling survival. Beyond cancer, mitochondrial dysfunction underlies aging, neurodegeneration, and metabolic disease. Understanding cancer-induced mitochondrial changes reveals how metabolism drives age-related disease. Interventions targeting mitochondrial dysfunction could simultaneously benefit cancer prevention and aging reversal—suggesting mitochondrial function is fundamental to healthy aging. Source: Uppsala University, Cell Metabolism 2025.

Phenotypic heterogeneity and plasticity—the ability of cancer cells to switch states—are crucial in colorectal cancer (CRC) progression, metastasis, and therapy resistance. However, the specific regulatory factors and signals from the tumor microenvironment (TME) that drive this adaptability have remained largely unknown. This study aimed to characterize these heterogeneous cancer cell states in both primary CRC and liver metastases, and to investigate the intrinsic and extrinsic factors that govern them. Methods: The researchers employed a combination of techniques, including single-cell multiomics (scRNA-seq, snMultiome RNA + ATAC-seq) and spatial transcriptomics to perform an in-depth analysis of patient-derived samples from both primary colorectal cancers and colorectal cancer liver metastases. Results: The study revealed several critical findings: Regenerative and Inflammatory States: Two distinct cancer cell states with regenerative (RECs) and inflammatory (iRECs) phenotypes were identified in both primary and metastatic CRC. These cells share characteristics with metastasis-initiating cells observed in mouse models. Hybrid Phenotype: An intermediate cell population displaying a hybrid regenerative and stem-like phenotype was also discovered. Key Regulators: The transcription factors AP−1 and NF−κB were identified as key drivers of these regenerative cell states. Spatial Organization: These regenerative cells were found predominantly at the invasive edge of primary tumors and within liver metastases, situated in an immunosuppressive niche. TME Interactions: The study uncovered specific ligand-receptor interactions, largely driven by cancer-associated fibroblasts (CAFs) and macrophages, that are predicted to activate and sustain these regenerative and inflammatory programs in cancer cells. Metastatic Conservation: Importantly, the diverse cancer cell states observed in primary CRC were found to be largely re-established in liver metastases, suggesting that disseminated cells can recreate the primary tumor's heterogeneity at distant sites. Conclusion: This research significantly advances our understanding of the cellular and molecular underpinnings of CRC metastasis. By identifying distinct cancer cell states, their key transcriptional regulators (AP−1 and NF−κB), and the influential signals from the TME, this work uncovers potential vulnerabilities. These findings highlight factors that could serve as novel therapeutic targets aimed at impairing the metastatic process by limiting cancer cell plasticity and disrupting the supportive tumor microenvironment. Phenotypic heterogeneity and plasticity in colorectal cancer metastasis https://lnkd.in/gcU6i_vj Paper and research by @Samuel Ogden and larger team

Cancer cells do not just grow. They recycle, adapt, and survive. ♻️🧬 One of the key survival systems involved is autophagy — the cell’s internal recycling pathway. Autophagy normally helps healthy cells clear damaged components, recycle nutrients, and survive stress. But in cancer, this process can become complicated. Sometimes autophagy can help suppress tumour formation by removing damaged organelles and reducing cellular stress. But once a tumour is established, cancer cells may hijack autophagy to survive harsh conditions like: ⚠️ Low oxygen ⚠️ Nutrient deprivation ⚠️ Chemotherapy stress ⚠️ Metabolic pressure The pathway is tightly controlled by major cancer signalling networks: 🔹 PI3K/Akt signalling 🔹 mTOR signalling 🔹 MAPK/ERK signalling 🔹 p53 regulation 🔹 ATG proteins involved in autophagosome formation The process moves through stages: 1️⃣ Initiation 2️⃣ Elongation 3️⃣ Maturation 4️⃣ Autophagosome formation 5️⃣ Breakdown and recycling of cellular material What makes autophagy so fascinating is its dual personality. It can act like a cleanup crew. But in cancer, it can also become a survival strategy. That is why researchers are exploring whether targeting autophagy could make cancer cells more vulnerable to treatment. Because sometimes the key to fighting cancer is not only blocking growth signals… It is cutting off the backup systems cancer cells depend on when they are under attack. 🎯🔥 Cancer does not survive by accident. It survives by adapting. And autophagy is one of its most powerful adaptation tools. #CancerResearch #Autophagy #Oncology #CancerBiology #mTOR #PI3KAKT #CellBiology #TargetedTherapy #PrecisionMedicine #MedicalEducation #ScienceCommunication *Taken from BioRender for Educational Purposes*

METABOLIC REPROGRAMMING OF TUMOR MICROENVIRONMENT THROUGH MITOCHONDRIAL TRANSFER Over a century ago, Otto Warburg first demonstrated the mitochondria role in regulation of essential eukaryotic cellular processes, such as proliferation, death, metabolic adaptation, and calcium (Ca2+) homeostasis. Additionaly, it's critical in fatty acid oxidation (FAO), the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), gluconeogenesis, ketogenesis, heme biosynthesis, and iron-sulfur (Fe/S) cluster formation. As a result, mitochondrial dysfunctions participate in a series of diseases, including cancer. There are at least five mechanisms by which mitochondria contribute to the development of the malignant phenotype, including metabolic reprogramming of cancer cells - mitochondrial DNA mutations; oxidative stress - ROS, primarily produced by mitochondria; regulation of cell apoptosis, necrosis, and necroptosis (regulated form of necrosis that requires mtROS generation and depends on mitochondrial permeability transition); metabolic reprogramming; and sustained cellular proliferation. The tumor microenvironment (TME) is well-recognized in interactions between cancer and immune cells. Cancer cells within the TEM utilize various mechanisms to evade the immune system, particularly T cell attacks. They can manipulate the TME to suppress tumor-infiltrating lymphocytes (TILs), immune cells tasked with attacking tumors. Mitochondria, often referred to as the "powerhouse of the cell," generate energy for various cellular functions and play a key role in the metabolic reprogramming of both cancer cells and TILs, impair antitumor immune responses. However, the detailed mechanisms of these processes remain unclear. The team of researchers from Okayama University has uncovered novel insights into mitochondrial dysfunction in cancer immune evasion. In this study, researchers analyzed clinical specimens and identified mitochondrial DNA (mtDNA) mutations in TILs that present in cancer cells. Particularly, cancer cells mitochondria with mtDNA mutations can transfer it to the TILs. Normally, mitochondria in TILs undergo mitophagy through reactive oxygen species, but mitochondria transferred from cancer cells do not. This is due to the presence of mitophagy-inhibitory molecules, which attach to the mitochondria and are transferred to TILs, resulting in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This leads to impaired antitumor immunity both in vitro and in vivo. The presence of an mtDNA mutation in tumor tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer that may contribute to future cancer immunotherapies. #https://lnkd.in/e7CJXUJY #https://lnkd.in/eKkSx8nG

A striking new Nature Magazine paper sharpens an increasingly important concept in cancer biology: oncogenic epithelial cells do not merely adapt to a permissive microenvironment — they actively instruct its formation. Using integrated single-cell, spatial, and functional approaches, the study shows that KRASG12D-mutant alveolar type II cells rapidly enter regenerative-like states that function as signaling hubs, coordinating stromal and immune reprogramming at the very earliest stages of lung tumorigenesis. Through amphiregulin secretion, these mutant epithelial cells activate EGFR signaling in neighboring fibroblasts, inducing an injury-like fibrotic program. Those fibroblasts then expand and reprogram alveolar macrophages, amplifying inflammatory signaling and reinforcing epithelial plasticity. The result is a self-sustaining epithelial-stromal-immune circuit that establishes a tumor-permissive niche before overt malignant outgrowth. What is especially compelling is that disruption of the amphiregulin-EGFR axis prevented early niche formation and abrogated tumor initiation, highlighting a potentially actionable vulnerability at a stage of disease we still understand far too incompletely. More broadly, this work reinforces a principle that is gaining increasing traction across cancer types: oncogenic events within incipient tumor cells can direct surrounding normal tissues to build the very ecosystem required for tumor emergence. It echoes, in a different biological context, our earlier work showing that oncogenic HRAS can instruct the surrounding melanoma microenvironment to support tumorigenesis, in that case through induction of angiogenesis (Chin et al Nature 1999). An elegant and important study. Check it out. https://lnkd.in/g3wX289i

Breaking Study | #DendriticCells #Type1 control the formation, maintenance, & function of #TertiaryLymphoidStructures in #Cancer | Targeting of #cDC1s to enhance #TLS function & boost #Immunotherapy treatment modalities | #ICB | Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Here*, using spatial transcriptomics and multiplex imaging across various human tumors, Miriam Merad, MD, PhD & Co. found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting them to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, they developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+ progenitor exhausted CD8+ T cells (Tpex). They show that, during the early stages of tumor development, TLS formation relies on IFNγ-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+ and CD8+ T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer. *https://lnkd.in/e8GsCEfi Celentyx Ltd #immunooncology #drugdiscovery #CRO www.celentyx.com Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady Zhi Li FIGURE | Taken from Catherine Sautes-Fridman et al | The composition and function of tertiary lymphoid structures in cancer | https://lnkd.in/e5QKQ2aM |

Cancer often shows up in lab work before it shows up on imaging. By the time a tumor is large enough to be seen on a scan, the internal environment that allowed it to grow has often been altered for years. Some of the patterns I frequently see: 1. Iron overload. Ferritin creeping above 150-200. Elevated transferrin saturation. Excess iron fuels oxidative stress and lipid peroxidation—pro-growth environment. 2. Elevated estradiol (especially unopposed) High estradiol relative to progesterone. This can manifest as fibrocystic tissue, heavy cycles, etc. Estradiol is proliferative when not balanced with progesterone. 3. Low thyroid function. Thyroid is required for oxidative metabolism. When thyroid function slows, cells rely more heavily on glycolysis—a metabolic shift seen in many cancers. 4. Low progesterone. Progesterone is calming, anti-inflammatory, and supports thyroid function. It opposes estrogen-driven cellular proliferation, which is a feature of many cancers. Chronic stress and high estrogen which deplete progesterone is a pattern I see constantly before diagnosis. 5. Low magnesium. Magnesium is required for ATP stability and DNA repair. Chronic deficiency affects hundreds of enzymatic reactions. It is often depleted under stress. 6. Blood sugar dysregulation. Insulin and IGF-1 are growth signals. 7. Low vitamin D. Vitamin D regulates immune surveillance and cellular differentiation. Low levels can inhibit the body's ability to detect abnormal cells early. In one study of newly diagnosed breast cancer patients, 65-70% of women were deficient vitamin D (Zemlin et al., 2023). 8. Elevated prolactin (outside of breast feeding). Often stress-driven, prolactin can act as a growth factor in certain tissues, not just a hormone for lactation. 9. Prolonged emotional stress. Most of my patients have experienced intense emotional stress for a long period. The mind and body are entirely connected, so at the center we use EVOX therapy to help address the emotional terrain of each patient. 10. High cortisol. When cortisol is elevated for months or years, it suppresses the immune system, raises blood sugar, breaks down muscle, and lowers thyroid and progesterone. It's one of the most consistent patterns I see.

Not all cells with cancer-linked mutations turn into tumors—so what makes some vulnerable while others stay normal? A new study from researchers at Sinai Health in Toronto has found that the key may lie in how fast a cell divides. They discovered that cells with a shorter total cell cycle duration (Tc)—the time it takes to complete a full division—are much more likely to develop into tumors. This insight could help explain why cancer arises in some tissues but not others, even when the same dangerous mutations are present. The team started with retinoblastoma, a childhood eye cancer caused by mutations in the Rb gene. They found that mice with mutated Rb genes developed tumors only in specific areas—like the pituitary gland—even though the same mutated cells were present throughout the body. When researchers looked deeper, they noticed that the cells that turned cancerous all had shorter division cycles. This trend was consistent across multiple tissues and various mutations, including ones commonly seen in lung and skin cancers. Even more interesting, slowing down a cell’s cycle—even without triggering cell death or immune clearance—was enough to stop tumors from forming. Blocking the SKP2–p27–CDK2/CDK1 pathway slowed division and prevented cancer, without changing the cell’s other behaviors. This finding shifts the focus away from only genetic mutations or immune evasion, and toward the role of a cell’s behavior after mutation—especially how fast it divides. The researchers believe this discovery could change how we think about cancer’s origins and even help identify the specific “cell of origin” in various cancers. It also opens the door to new ways of preventing cancer by targeting cell division speed, offering a fresh approach beyond traditional treatments. Research Paper 📄 https://lnkd.in/eNSWNwvu

🔬 What if the same molecule that helps your body heal a wound is also helping cancer grow? A new mini review published in Frontiers in Cell and Developmental Biology reveals a fascinating and overlooked connection. Here's the story. When tissue is injured, cells called pericytes activate and transform into mesenchymal stromal cells (MSCs). These MSCs then produce molecules called pregnancy specific glycoproteins, or PSGs. The numbers are striking: PSG3 expression jumps 820 fold and PSG8 rises 299 fold in MSCs compared to their pericyte precursors. 🧬 What do these PSGs do? They act on macrophages, pushing them toward an M2 phenotype. M2 macrophages are the "repair crew" of the immune system. They reduce inflammation, promote new blood vessel formation, and help rebuild tissue. Sounds great, right? ✅ In wound healing, it is. M2 macrophages create a regenerative environment that restores damaged tissue. 🚨 But in cancer, this same mechanism may backfire. Tumors behave like wounds that never heal. Cancer associated fibroblasts (up to 85% of which can originate from pericytes in liver cancer models) may keep producing PSGs, maintaining a cycle of TGFβ production and M2 polarization that suppresses the immune response. This creates a microenvironment where CD8+ T cells are excluded and even CAR T cell therapies struggle to work against solid tumors. 💡 The bold proposal: PSGs could be a novel therapeutic target upstream of TGFβ. Blocking them might restore immune access to tumors and enhance the effectiveness of CAR T cell therapy. This hypothesis is still inferential, but the evidence framework is compelling and the testable predictions are clearly outlined. Sometimes the biggest breakthroughs come from revisiting molecules we thought we already understood. 📄 da Silva Meirelles L (2026), Frontiers in Cell and Developmental Biology 🔗 doi: 10.3389/fcell.2026.1798621 #CellBiology #Cancer #Immunology #MSCs #TumorMicroenvironment #CARTcells #TGFbeta #MacrophagePolarization #Oncology #StemCells #Science #Research