Biology subjects

Podsypanina, K.

Publications and source records attributed to Podsypanina, K..

5 recordsLinked to original sources

bioRxiv2026

Toll-like receptor 9 contributes in microglial activation and lysosomal dysfunction to promote Alzheimer disease

Toll like receptor 9 (TLR9) is an endosomal-lysosomal innate immune receptor which recognizes microbial and host-derived double-stranded DNA (dsDNA) to induce cellular immunity. TLR9 pathway has been implicated in Alzheimers disease (AD) pathology via its ability to modulate peripheral immune cells but its exact role in the central nervous system (CNS) remains unclear. Here we show that extranuclear dsDNA accumulating in human AD brain and in a mouse model of AD, together with microglia around amyloid-{beta} (A{beta}) plaques stimulates TLR9 in vitro. Loss of TLR9 inhibits the transition of homeostatic microglia to reactive microglia, a cell type associated with a chronic pro-inflammatory state, promoting their reprogramming into an anti-inflammatory state, thereby restoring lysosomal integrity required for A{beta} peptides degradation. Predisposition to lysosome permeabilization could be mimicked with repeated TLR9 stimulation using CpG-A ODNs in a human microglial cell line and was rescued with TLR9 inhibition. Furthermore, lack of TLR9 protects mice developing AD from cognitive defects and neuronal loss. A{beta} pathology is also reduced specifically in male mice. Altogether, our results have identified a critical role of TLR9 in AD, where it modulates microglial activation and lysosome function to interfere with the progression of AD. These findings suggest that targeting TLR9 signaling and lysosomal function may be a relevant strategic approach to reduce AD pathology.

immunology↗

bioRxiv2025

SPARC is a new driver of early breast tumor progression via TGF-β -dependent mechanism.

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor of invasive ductal carcinoma (IDC). The challenge lies in discriminating between DCIS progressors and DCIS non-progressors, often resulting in over- or under-treatment in many cases. Membrane type 1 (MT1)-matrix metalloproteinase (MMP) has been previously identified as an essential gene involved in DCIS progression. Here, RNA-sequencing analysis of MT1-MMPhigh subpopulation derived from invasive breast tumors in the intraductal xenograft model was compared against a dataset of human high-grade DCIS, and Secreted Protein Acidic and Cysteine Rich (SPARC) has emerged as a master candidate involved in early breast tumor progression. We report that SPARC is up-regulated in DCIS as compared to normal breast epithelial tissues, and further increased in IDC relative to synchronous DCIS foci. We found a positive correlation between SPARC and MT1-MMP expression in DCIS lesions. At the mechanistic level, depletion of SPARC reduced MT1-MMP expression, the degradative capacity of the cells and the activation of the TGF-{beta} signalling canonical pathway. Pharmacological inhibition of the TGF-{beta} signalling pathway decreased SPARC and MT1-MMP at the mRNA and protein level, and concomitantly the cell degradative capacity and 3D cell migration. Strikingly, inhibition of the TGF-{beta} signalling pathway limits the invasive transition of breast tumors in a new triple-negative mouse intraductal syngeneic xenograft model. Moreover, high SPARC expression was positively correlated with both, TGF-{beta} and its receptor, TGFBRI, in a basal type of breast cancer collection supporting our findings. This study identifies SPARC as a new driver of early breast tumor progression via a TGF-{beta}-dependent mechanism, suggesting TGF-{beta} signaling pathway as a potential target for patients with high SPARC expression.

cancer biology↗

bioRxiv2024

Application of the AMOCATI R workflow to tumor transcriptomic data delineates the adverse effect of immune cell infiltration in immune-privileged organs

Immune cells are present inside tumor tissue and can alter tumor growth. Expression profiles of human tumors hold transcripts from cancer cells and their microenvironment, including the infiltrating immune cells. Few standardized methods examine tumor immunobiology relying only on tumor transcriptome data. Using a new in-house developed R analysis workflow called AMOCATI, we classified 43 cancer types from 11,176 patients according to the degree of infiltration by 18 distinct immune cell subsets, measured by the abundance of their transcriptomic signature, and calculated its effect on the disease outcome. In about half of cancers affecting organs without immune privilege, immune cell infiltration has beneficial effects. In contrast, immune infiltration in cancers of immune-privileged organs (eye, testis and brain) confers poor prognosis. Moreover, transcriptional evidence of increased immune cell activity in immune-privileged cancer sites is associated with bad prognosis. Thus, our results suggest that the effect of immune infiltration may depend on the origin of the primary tumor. SIGNIFICANCEOur in-house developed computational R approach AMOCATI allows to easily download public transcriptomic and clinical data, classify and analyze them. AMOCATI permitted us to define gene expression signatures associated with short- or long-term survival from 11,176 untreated patient unsorted biopsies in 43 types of cancer. We present the level of infiltration of 18 types of immune cell subsets transcriptomic signatures and 50 immune-related pathways in all these cancers Correlation between immune infiltration of the tumor and survival establishes a link between tumor tissue of origin and the overall effect of immune infiltration on survival. Immune cell infiltration in tumors from immune privileged organs correlate with shorter survival. Contrary to what we observe in hot tumors, biological pathways of immune response are associated with a short-term survival profile in these cancers.

cancer biology↗

bioRxiv2020

CENP-A overexpression drives distinct cell fates depending on p53 status

Tumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays and single-cell RNA-sequencing over time, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. But, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential precursor for tumour cell invasion and metastasis. Thus, CENP-A overexpression drives distinct cell fates depending on p53 status, with important implications for tumour evolution.

cancer biology↗

bioRxiv2016

An evolving cancer instigates clonally unrelated neighboring cells to form distant metastases.

Based on the clonal evolution theory of cancer formation, a single cell within a tissue gains a cancer-driving mutation and thus a growth advantage. From this expanded cellular mass, another cell gains a new mutation allowing this newly mutated cell to gain new competitive advantage and to expand in number (thus clonal expansion). Another clone then emerges. Eventually all required mutations are gained, and a cancer forms. Consequently, while a primary lesion may harbor divergent subclones, all the subclones within the primary cancer as well as all metastatic growths in secondary organs share at least the very first oncogenic mutation that initiates the primary cancer. However, by tracking genetically marked mammary epithelial cells that suffered the initiating oncogenic mutation--and their neighboring mammary cells that did not-in several mouse models of human breast cancer, we found that genetically unrelated mammary epithelial cells can be colluded by neighboring mutated cells to disseminate, and that they can even undergo de novo tumorigenic transformation and form distant metastases. Therefore, clonally unrelated epithelial cells may contribute to cancer progression and to the heterogeneity of the systemic disease. The non-linear cancer spread has important implications in cancer prevention, treatment, and therapeutic resistance.

cancer biology↗