Biology subjects

Malanchi, I.

Publications and source records attributed to Malanchi, I..

11 recordsLinked to original sources

bioRxiv2026

A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth

How inflammation shapes acute myeloid leukaemia (AML) has come under scrutiny, as it may explain the disease resistance to immunotherapy approaches. IFNg has emerged as a key cytokine with paradoxical roles in suppressing and supporting AML growth, and the fundamental question of how leukemic stem cells (LSCs) respond to IFNg and whether IFNg signaling influences LSC quiescence and their capacity to regenerate disease over the long term remains unanswered. Here, we study primary human AML cells and murine models and combine bioinformatics analyses and functional assays to show that AML hierarchical heterogeneity is responsive to IFNg challenge. We uncover that IFNg triggers parallel stemness and differentiation programs; HSC/MPP-like cells enter deeper stemness, associated with quiescence and high leukaemia regeneration potential, while the surviving pool of progenitor-like cells divides faster but produces progeny that is quickly lost. Finally, with murine models we show that exposure to inflammation in vivo results in only transient impairment of leukaemia propagating capacity. This mechanism is driven by a previously unrecognised intraclonal fate bifurcation, relevant for the development of more effective therapeutic approaches.

cancer biology↗

bioRxiv2026

Sex-Dimorphic Neural Memory Shapes Pancreatic Tissue Resilience

Epithelial cells can encode prior damage into lasting epigenetic and functional states, enabling a primed response to future insults. In the pancreas, acute injury induces reversible acinar cell reprogramming toward a progenitor-like identity that persists beyond repair, supporting resilience to recurrent injury but creating a permissive state for malignant transformation. Given the central role of the tissue niche in stem cell regulation, we investigated microenvironmental adaptations that sustain this primed epithelial state. Using genetic mouse models and ex vivo organoid co-cultures, we identify a sex-specific sensory neural memory after pancreatitis that sustains long-term epithelial plasticity through a CGRP-dependent neuron-epithelial axis. We show that sex differences in acute inflammation drive neutrophil-dependent suppression of neural activation in females, decoupling neural memory from epithelial plasticity after repair. In males, neural memory promotes post-injury plasticity, revealing tissue memory as coordinated adaptation between epithelial progenitors and their niche.

cancer biology↗

bioRxiv2026

An injectable soft implant for long-acting, reversible, ultra-stable release of therapeutics

Providing long-term (>6 months) zero-order drug release from easily administered formulations is a key challenge in improving patient adherence and facilitating access. Herein, we report the design and development of an injectable, biodegradable, long-acting polymeric microparticle-embedded hydrogel platform for prolonged, zero-order release of therapeutics. This "soft implant" is injectable for ease of administration and can be retrieved via a small incision, allowing for discontinuation of therapy if desired. Central to the platform are surface-eroding poly(orthoester) (POE) microparticles, which were molecularly tailored to tune zero-order drug release across a wide range of timeframes. We demonstrate the clinical potential of the "soft implant" using levonorgestrel, a contraceptive agent requiring sustained dosing. In vitro, we observed zero-order release for 300 days, projected for >12 months, with behavior consistent with surface erosion further supported through Raman chemical mapping. In vivo studies confirmed zero-order release for six months, projected to 12 months, from a subcutaneous injection in rats. We envision that our platform could transform therapies that require long-term, regular drug dosing, significantly improving compliance and therapy outcomes.

bioengineering↗

bioRxiv2025

Inhibition of neutrophil degranulation by Nexinhib20 delays the development of radiation-induced pulmonary fibrosis

Despite advances in radiation delivery techniques that enhance tumour targeting and minimise collateral exposure, healthy tissues remain susceptible to radiation-induced fibrosis, a chronic and progressive condition that can severely compromise patient quality of life. Therapeutic options to prevent or treat radiation-induced fibrosis remain limited. Recent work has shown that neutrophils infiltrating healthy lung tissue after irradiation adopt an activated phenotype capable of perturbing cellular responses of both epithelial and mesenchymal cells. However, the contribution of these radiation-educated neutrophils to the development of radiation-induced fibrosis remains unclear. Using targeted, image-guided lung irradiation to deliver a dose sufficient to induce fibrosis within four months, we demonstrate that neutrophils are essential for the efficient development of clinically evident fibrosis. Lung irradiation educates neutrophils, enabling them to promote early alterations in the extracellular matrix shortly after radiation exposure. We further show that this "educated" phenotype depends on neutrophil degranulation activity. Pharmacological inhibition of degranulation with Nexinhib20 redirected these cells toward a pro-angiogenic and anti-fibrotic phenotype. Importantly, this treatment was also associated with a transcriptional shift in mesenchymal cells away from a pro-fibrotic program, resulting in a marked delay in the onset of radiation-induced fibrosis. Importantly, Nexinhib20 did not impair the efficacy of cancer radiotherapy, underscoring its potential as a therapeutic strategy to prevent fibrotic complications without diminishing anti-tumour effectiveness.

cancer biology↗

bioRxiv2025

Cancer-driven neutrophil priming couples systemic epithelial regenerative programs with pre-metastatic niche formation

Cancer progression involves systemic changes that extend beyond the primary tumour. Through cancer-induced systemic conditioning, breast tumours generate subclinical alterations in distant organs that facilitate metastatic seeding and pre-metastatic niche formation. Neutrophils, mobilized through cancer-driven emergency granulopoiesis, actively contribute to this process. In this study we extend the concept of neutrophil-dependent conditioning beyond pre-metastatic sites, uncovering a broader systemic regenerative activation that links inflammation, tissue regeneration, and metastasis. This activation manifests as enhanced epithelial progenitor activity, measured by increased organoid formation, across multiple organs, including those with low risk of breast cancer metastasis. This neutrophil-dependent perturbation in lung alveolar progenitors and intestinal epithelial lineage commitment, is an indication of an altered organ physiology, enhancing tissue resilience to injury. Moreover, we identify UPP1 expression, which exclusively characterizes neutrophils generated through emergency granulopoiesis, as a key factor sustaining high translational activity in neutrophil progenitors and enabling the full acquisition of cancer-primed properties. Consequently, neutrophil loss of UPP1 reduces both their lung pro-metastatic function and their capacity to activate alveolar progenitors. Mechanistically, this involves interactions between cancer-primed neutrophils and platelets, which localize within lung interstitial spaces near alveolar cells to stimulate epithelial progenitor activity. Together, these findings uncover a previously unrecognized tumour-induced systemic conditioning in which neutrophils coordinate epithelial regenerative activation as part of a pro-metastatic epithelial niche, with UPP1 as a key determinant of their cancer-primed state.

cancer biology↗

bioRxiv2025

Splenic granulopoiesis and S100A9 drive resistance to checkpoint inhibitors conferred by liver metastases

Here, we investigate why liver metastases reduce the efficacy of immune checkpoint inhibitors (CPI). The poor prognosis of patients with liver metastases is associated with a systemic increase in neutrophils. Using experimental models, we confirm that mice with liver metastases respond poorly to CPI, have elevated neutrophils and suppress the response of subcutaneous lesions to CPI. We demonstrate that liver metastases, acting partly via IL-6, boost granulopoiesis in the spleen and promote the generation of immature S100A9hi neutrophils that suppress T-cell proliferation. Human liver metastases exhibit a similar increase in S100A9hi neutrophils. Neutrophil depletion attenuates the growth of liver metastases, but not subcutaneous metastases. Moreover, genetic deletion of S100A9 enables liver metastases to be effectively treated with CPI, and prevents liver metastases from suppressing the response in subcutaneous metastases. Thus, we document how liver metastases specifically change splenic granulopoiesis leading to changes in the microenvironment of non-hepatic lesions, and how targeting a key neutrophil protein restores the efficacy of CPI.

immunology↗

bioRxiv2024

Type I interferons induced upon respiratory viral infection impair lung metastatic initiation

Invasive breast cancer accounts for 7% of all cancer-related deaths, with the lungs being a common site of metastases. At the same time, lower respiratory tract infections are a common cause of morbidity and mortality worldwide. Acute viral respiratory infections induce transitional changes in the lung; however, the impact of these changes on metastasis initiation and cancer progression remains unclear. Using primary murine MMTV-PyMT breast cancer cells in an experimental lung metastasis model, we show that changes induced by respiratory syncytial virus (RSV) infection impair tumor cell seeding and early establishment in the lung, resulting in lower number of metastatic nodules. Furthermore, we demonstrate that this reduction of metastases is due to alterations in the lung environment mediated by type I interferons (IFNs) that are produced in response to RSV infection. Consistent with that notion, intranasal administration of recombinant IFN- recapitulates the anti-tumor effect of RSV infection. Type I IFNs change the lung cellular composition and induce an Interferon Stimulated Gene (ISG) driven response, creating an alveolar environment that is less supportive of tumor cell growth. Indeed, epithelial cells from mice infected with RSV or intranasally exposed to IFN-, are less supportive of tumor cell growth ex vivo. Altogether, our results suggest that type I IFNs induced by infection with some respiratory viruses perturb the lungs and consequently interfere with the ability of tumor cells to successfully initiate metastatic colonization. SignificanceWomen diagnosed with metastatic breast cancer have a low survival rate. The lungs are a common metastatic site and are constantly exposed to viral pathogens, such as coronavirus, RSV and influenza virus. Thus, breast cancer and respiratory virus infection are likely to co-occur, but their interplay remains unclear. We show that type I interferons (IFNs), induced upon viral infection impair metastatic cancer cell seeding of mouse lungs. This is potentially via an effect of IFNs on lung epithelial cells, which become less supportive of early tumor cell proliferation. These findings indicate that viral infections and type I IFNs can alter the lung environment and impair implantation of metastatic cells, which could be explored to improve future cancer treatments.

immunology↗

bioRxiv2024

Mapping the niche of breast cancer metastases in lung and liver

Breast cancer progression to visceral organs such as lung and liver is regarded as a dreadful event, unequivocally associated with a poor prognosis. Yet, these vital sites are characterized by highly diverse cellular microenvironments and physiological functions, suggesting that they may influence cancer cells behavior in divergent ways. Unexpectedly, we find that while the liver microenvironment fosters metastasis-promoting properties and boosts secondary spread, the lungs impose a roadblock to the same processes. Using patient data and tissues from rapid autopsy, as well as mouse models with barcode-mediated metastasis tracing, niche labeling technology and single cell analysis of both tumor cells and their direct microenvironment, we dissect cellular and molecular microenvironmental factors that impose this differential behavior. Among these, we identify BMP2-producing endothelial cells as critical players within the liver metastatic niche, capable to enhance metastasis-to-metastasis dissemination. Targeting BMP2 receptor on breast cancer cells suppresses their metastasis-forming ability. Altogether, we reveal a contrast in the site-specific behavior of lung and liver metastases in breast cancer, highlighting microenvironmental factors that contribute to this diversity, as well as organ-specific opportunities for intervention.

cancer biology↗

bioRxiv2023

Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes

PurposeA high number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear. Patients and MethodsHere, we investigate changes in circulating neutrophils from newly diagnosed breast cancer patients before any therapeutic interventions. To do this, we assessed their lifespan and their broader intracellular kinase network activation states by using the Pamgene Kinome assay which measures the activity of neutrophil kinases. ResultsWe found sub-type specific L-selectin (CD62L) changes in circulating neutrophils as well as perturbations in their overall global kinase activity. Strikingly, breast cancer patients of different subtypes (HR+, HER2+, triple negative) exhibited distinct neutrophil kinase activity patterns indicating that quantifiable perturbations can be detected in circulating neutrophils from early breast cancer patients, that are sensitive to both hormonal and HER-2 status. We also detected an increase in neutrophils lifespan in cancer patients, independently of tumour subtype. ConclusionsOur results suggest that the tumour-specific kinase activation patterns in circulating neutrophils may be used in conjunction with other markers to identify patients with cancer from those harbouring only benign lesions of the breast. Given the important role neutrophil in breast cancer progression, the significance of this sub-type of specific priming warrants further investigation. Clinical RelevanceThe current study aims to investigate cancer-specific changes in circulating neutrophils in patients with newly diagnosed early breast cancer before any therapeutic intervention. We found L-selectin (CD62L) changes in circulating neutrophils from patients with early-stage breast cancer compared to healthy volunteers, which is an indication of an early phenotypical change. Moreover, these changes in CD62L were dependent on the breast cancer sub-type, showing opposing trends according to the hormonal receptor status of the tumour. Importantly, this subtype dependent phenotypic alteration was reflected in broader intracellular signalling perturbation when measuring intracellular kinase activity. Moreover, those cancer perturbed neutrophils, show expanded life span when cultured ex vivo, suggesting an alteration in their physiologic state. The tumour-specific kinase activation patterns in circulating neutrophils may be useful in conjunction with other markers to distinguish patients with cancer from those with benign lesions of the breast.

cancer biology↗

bioRxiv2022

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation

Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-{kappa}B subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-{kappa}B signaling.

cancer biology↗

bioRxiv2021

Early mismatch between cancer cells and their tumour microenvironment blocks long term growth

Cancer cells thrive embedded in a fine-tuned cellular and extracellular environment or tumour microenvironment (TME). There is a general understanding of a co-evolution between cancer cells and their surrounding TME, pointing at a functional connection between cancer cells characteristics and the perturbations induced in their surrounding tissue. However, whether this functional connection needs to be set from the start or if aggressive cancer cells can always be dominating their microenvironment has never been formally proven with a dedicated experimental setting where malignant cells can be challenged to grow in a different TME from the one they would naturally create. Here we generated an experimental setting where we transiently perturb the secretory profile of aggressive breast cancer cells without affecting their intrinsic growth ability. This led to the initial establishment of an atypical TME. Interestingly, even if initially tumours are formed, this atypical TME evolves to impair long term in vivo cancer growth. Using a combination of in vivo transcriptomics, protein arrays and in vitro co-cultures, we found that the atypical TME culminates in the infiltration of macrophages with STAT1high activity. These macrophages show strong anti-tumoural functions which reduce long-term tumour growth, despite lacking canonical M1 markers. Importantly, gene signatures of the mesenchymal compartment of the TME, as well as the anti-tumoural macrophages show striking prognostic power-correlating with less aggressive human breast cancers.

cancer biology↗