IL-1 and senescence: Friends and foe of EGFR neutralization and immunotherapy

Historically, senescence has been considered a safe program in response to multiple stresses in which cells undergo irreversible growth arrest. This process is characterized by morphological and metabolic changes, heterochromatin formation, and secretion of inflammatory components, known as senescence-associated secretory phenotype (SASP). However, recent reports demonstrated that anti-cancer therapy itself can stimulate a senescence response in tumor cells, the so-called therapy-induced senescence (TIS), which may represent a temporary bypass pathway that promotes drug resistance. In this context, several studies have shown that EGFR blockage, by TKIs or moAbs, promotes TIS by increasing IL-1 cytokine production, thus pushing cells into a "pseudo-senescent" state. Today, senotherapeutic agents are emerging as a potential strategy in cancer treatment thanks to their dual role in annihilating senescent cells and simultaneously preventing their awakening into a resistant and aggressive form. Here, we summarize classic and recent findings about the cellular processes driving senescence and SASP, and we provide a state-of-the-art of the anti-cancer strategies available so far that exploits the activation and/or blockade of senescence-based mechanisms

Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

ERBB4 is a tyrosine kinase receptor reported to exert both oncogenic and tumor suppressor activities. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms. By stratifying breast cancer patients for clinical and molecular subtypes and ERBB4 mRNA abundance, we here report that higher ERBB4 levels correlate with longer relapse-free survival in breast cancer patients of HER2-enriched and luminal A molecular subtypes, proposing a cancer-protecting role for this receptor in these specific subgroups. We also observed that HER2-enriched breast cancers express intermediate ERBB4 mRNA levels compared to luminal and triple-negative/basal-like subgroups, which displayed the highest and the lowest levels, respectively. Inspired by these clinical data, we tested the activation of ERBB4 by Neuregulins as a potential anticancer strategy for HER2+ breast cancers. To this end, we employed two HER2+ breast cancer cellular models (BT474 and SKBR3), which express intermediate/high and low ERBB4 levels, respectively. Cell proliferation and motility were evaluated on these cellular models following treatments with Neuregulin 1 (NRG1), which activates both ERBB3 and ERBB4, or Neuregulin 4 (NRG4), which specifically activates ERBB4. Both NRG1 and NRG4 were used alone or in combination with anti-ERBB2 neutralizing antibodies, namely trastuzumab and pertuzumab. In vitro treatment with NRG1 on BT474 cells restrained cell growth and reduced the anti-proliferative efficacy of trastuzumab. In contrast, treatment with NRG1 on SKBR3 cells increased cell proliferation and migration, and partially or completely impaired the anti-proliferative/anti-migratory action of trastuzumab and/or pertuzumab. Importantly, in both the cell lines, treatment with NRG4 robustly potentiated the anti-proliferative action of trastuzumab and pertuzumab. Collectively, our data in HER2+ breast cancer cells highlight that NRG1 may exert both pro- and anti-proliferative effects, and may reduce the efficacy of anti-HER2 agents, whereas NRG4 may boost the anti-proliferative effects of anti-ERBB2 agents. We propose a provocative paradigm shift in the field of growth factors in cancer progression, suggesting the administration of ERBB4 ligands, such as Neuregulin 4, as a strategy to improve the efficacy of anti-ERBB2 agents

Beta-Catenin/HuR Post-Transcriptional Machinery Governs Cancer Stem Cell Features in Response to Hypoxia

Hypoxia has been long-time acknowledged as major cancer-promoting microenvironment. In such an energy-restrictive condition, post-transcriptional mechanisms gain importance over the energy-expensive gene transcription machinery. Here we show that the onset of hypoxia-induced cancer stem cell features requires the beta-catenin-dependent post-transcriptional up-regulation of CA9 and SNAI2 gene expression. In response to hypoxia, beta-catenin moves from the plasma membrane to the cytoplasm where it binds and stabilizes SNAI2 and CA9 mRNAs, in cooperation with the mRNA stabilizing protein HuR. We also provide evidence that the post-transcriptional activity of cytoplasmic beta-catenin operates under normoxia in basal-like/triple-negative breast cancer cells, where the beta-catenin knockdown suppresses the stem cell phenotype in vitro and tumor growth in vivo. In such cells, we unravel the generalized involvement of the beta-catenin-driven machinery in the stabilization of EGF-induced mRNAs, including the cancer stem cell regulator IL6. Our study highlights the crucial role of post-transcriptional mechanisms in the maintenance/acquisition of cancer stem cell features and suggests that the hindrance of cytoplasmic beta-catenin function may represent an unprecedented strategy for targeting breast cancer stem/basal-like cells

Neonatal Apex Resection Triggers Cardiomyocyte Proliferation, Neovascularization and Functional Recovery Despite Local Fibrosis

So far, opposing outcomes have been reported following neonatal apex resection in mice, questioning the validity of this injury model to investigate regenerative mechanisms. We performed a systematic evaluation, up to 180 days after surgery, of the pathophysiological events activated upon apex resection. In response to cardiac injury, we observed increased cardiomyocyte proliferation in remote and apex regions, neovascularization, and local fibrosis. In adulthood, resected hearts remain consistently shorter and display permanent fibrotic tissue deposition in the center of the resection plane, indicating limited apex regrowth. However, thickening of the left ventricle wall, explained by an upsurge in cardiomyocyte proliferation during the initial response to injury, compensated cardiomyocyte loss and supported normal systolic function. Thus, apex resection triggers both regenerative and reparative mechanisms, endorsing this injury model for studies aimed at promoting cardiomyocyte proliferation and/or downplaying fibrosis. In this article, Nascimento and colleagues demonstrate that neonatal apex resection stimulates cardiomyocyte proliferation and permanent scarring in the apex. Newly formed cardiomyocytes compensate muscle loss by resection, and resected hearts recover functional competence in adulthood. These findings endorse this model for studies aiming to block cardiac fibrosis and/or favoring CM proliferation