Biology subjects

Pietras, K.

Publications and source records attributed to Pietras, K..

7 recordsLinked to original sources

bioRxiv2026

Targeting cancer-associated fibroblasts for treatment of ER+ breast cancer: A mathematical modeling perspective and optimization of treatment strategies

Cancer-associated fibroblasts (CAFs) are a central component of the tumor microenvironment that facilitate a supportive niche for cancer progression and metastasis. Experimental evidence suggests that CAFs can facilitate estrogen-independent tumor growth, thereby reducing the efficacy of anti-hormonal therapies. Understanding and quantifying the complex interactions between tumor cells, hormonal signalling, and the microenvironment are crucial for designing more effective and individualized treatment strategies. We propose a mathematical framework to explore the influence of CAFs on ER+ breast cancer progression and to evaluate strategies to mitigate their impact. We develop a system of nonlinear ordinary differential equations that substantiates the experimental observations by providing a mechanistic basis for the role of CAFs in regulating estrogen-independent growth dynamics. We then employ optimal control theory to evaluate distinct therapeutic approaches involving monotherapy or combinations of: (i) inhibition of tumor-to-CAF signaling, (ii) inhibition of CAF-to-tumor proliferative signaling, and (iii) endocrine therapy. Taken together, our results demonstrate that CAF-targeted strategies can enhance treatment efficacy across various estrogen dosing regimens. Our study provides new insights into the potential of CAF as a therapeutic target that could help to improve existing approaches for endocrine therapies.

systems biology↗

bioRxiv2025

Coevolution of neoplastic and non-neoplastic reactive astrocyte states converges on mesenchymal-like and injury-response programs during murine glioblastoma progression and post-radiotherapy recurrence

Glioblastomas initially respond to radiotherapy but invariably recur, often within high-dose radiation treatment fields. Although stromal radiation responses are incompletely understood, evidence suggests that the tumor microenvironment becomes tumor-supportive after therapy. Using a genetically engineered glioblastoma mouse model, we profiled healthy brain, primary tumors, and post-radiotherapy recurrences with single-cell and spatial transcriptomics and immunohistochemistry. Across 13 non-neoplastic cell types and 10 tumor cell states, we mapped transcriptional adaptations accompanying progression from healthy brain to primary and recurrent glioblastoma. We identified distinct astrocyte states linked to disease stage, including reactive non-neoplastic astrocytes and tumor cells adopting reactive astrocyte-like phenotypes. Reactive astrocyte-like tumor cells with mesenchymal and injury-response signatures were enriched after radiotherapy and persisted in recurrent tumors. Receptor-ligand interactions between reactive astrocytes and tumor cells included known and putative drivers of aggressiveness. These findings highlight convergent reactive astrocyte programs in astrocytes and tumor cells as potential mediators of glioblastoma radioresistance.

cancer biology↗

bioRxiv2024

Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma

Glioblastoma (GBM) is characterized by fast progression, an infiltrative growth pattern, and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a perivascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes, mural cells intimately associated with the endothelium, as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, endothelial cells deprived of pericyte association altered their signaling programs, which in turn attracted perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase MET on GBM cells harboring an extreme mesenchymal subtype driven by the key phenotypic regulator Fosl1 within hypoxic regions. Indeed, orthotopic implantation of isolated, MET-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype. In patients, low expression of a pericyte core gene signature was reduced in recurrent GBM, compared to primary tumors. Consistently, gene signatures for transcriptional programs of Fosl1+Met+ GBM cells were indicative of poor survival in human tumors, and spatial transcriptomics corroborated their superior invasive capacity. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/609765v1_ufig1.gif" ALT="Figure 1"> View larger version (102K): org.highwire.dtl.DTLVardef@803a8eorg.highwire.dtl.DTLVardef@8441eaorg.highwire.dtl.DTLVardef@1038288org.highwire.dtl.DTLVardef@16eccfc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

An ALK1-governed monocytic lineage shapes an immunosuppressive landscape inbreast cancer metastases

The biology centered around the TGF-{beta} type I receptor ALK1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy. Graphical abstractSee submitted file

cancer biology↗

bioRxiv2024

Hypoxia-induced Complement Component 3 Promotes Aggressive Tumor Growth in the Glioblastoma Microenvironment

Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single cell, and spatially resolved transcriptomic data from human GBM patients. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level-dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. Presence of C3 increased proliferation of GBM cells under hypoxic conditions, as well as clonal survival of GBM cells following radiation. Targeting C3aR using the antagonist SB290157 decreased GBM cell self-renewal in vitro, and prolonged survival of glioma bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM, and support a role of hypoxia-induced C3a-C3aR signaling as a contributor to glioma aggressiveness.

cancer biology↗

bioRxiv2022

Inherent evolutionary unpredictability in cancer model system

Despite the advent of personalized medicine, it is still difficult to predict how a cancer develops over time at the level of the individual patient or even in cancer model systems which begs the question whether certain aspects of cancer can ever be predicted or if there is an inherent unpredictability in cancer, similar to other complex biological systems, We demonstrate by a combination of agent-based mathematical modelling and analysis of data from patient-derived xenograft systems from multiple cancer types that certain conditions may invoke chaotic fluctuations in the clonal landscape of cancer cells. Our findings indicate that under those conditions, the cancer genome behaves as a complex dynamic system, making its long-term evolution inherently unpredictable.

evolutionary biology↗

bioRxiv2021

Infection of brain pericytes underlying neuropathology of COVID-19 patients

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFR{beta} in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.

pathology↗