Kristian Pietras

BackgroundHuman breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes—the other being interlobular fibroblasts. While cancer-associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship—if any—with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation.MethodsPrimary breast tumor-derived CAFs were transduced to express human telomerase reverse …

Immune checkpoint blockade (ICB) has improved outcome for metastatic melanoma patients but not all benefit from treatment. Several immune-and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a unique cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.

The complex interplay between genetically diverse tumor cells and their microenvironment significantly influences cancer progression and therapeutic responses. This review highlights recent findings on cellular plasticity and heterogeneity within the breast cancer ecosystem, focusing on the roles of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). We discuss evidence suggesting that breast cancer cells exhibit phenotypic plasticity driven by both intrinsic genetic factors and external microenvironmental cues, impacting treatment responses and disease recurrence. Moreover, single-cell RNA sequencing studies reveal diverse subtypes of CAFs and TAMs, each with distinct functional gene expression programs and spatial organization within the tumor microenvironment. Understanding the hierarchical relationships and niche cues governing cellular phenotypes offers new …

Introduction: Subsets of cancer-associated fibroblasts (CAFs) in colorectal cancer remain poorly characterized preventing their use as biomarkers and drug targets. Results: Integrated scRNA seq profiling and multiplex staining identified four human CAF subsets These were A1 (PDGFRA+/FAP-/TF), PDGFRAhighA2 (PDGFRA+/FAP+/TF-), PDGFRAlowA2 (PDGFRA-/FAP+/TF-) and A3 (PDGFRA+/FAP-/TF+) (TF: Tissue Factor).Spatial analyses identified spatial associations indicative of specific functional interactions of fibroblast subsets with cancer cells or immune cells. Explorative analyses in six CRC cases suggested, in general, favorable effects of FAP-negative subsets (A1 and A3) on immune features and cancer cell proliferation, whereas FAP-positive subsets PDGFRAhighA2 and PDGFRAlowA2 overall showed pro-tumoral associations. To extend findings, niches were quantitated in U-CAN cohort of …

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.

Glioblastoma multiforme (GBM) is characterized by fast progression, 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 peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes 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 …

Invariant natural killer T (iNKT) cells are part of the family of unconventional T cells, and they recognize glycolipid antigens presented on the MHC class I like molecule CD1 [1]. In humans there are five CD1 molecules named CD1a to CD1e, whereas mice use only CD1d for lipid presentation. Functionally, iNKT cells can elicit both cytotoxicity similarly to conventional CD8 T cells and secrete cytokines that influence the adaptive immune response including providing direct T cell help to B cells [2]. In the context of tumors, they can use both release of granzyme B and use Fasmediated mechanisms for killing of tumor cells. As iNKT cells use a restricted TCR repertoire and CD1 molecules are nonheterogenous the risk of graft vs host disease is limited and thus these T cells have been an attractive option for off the shelf immunotherapy to treat cancer [3]. So far clinical trials have mostly focused on using the glycolipid …

Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced …

Glioblastoma multiforme (GBM) is characterized by fast progression, 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 peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes 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 …

Around 10-15% of all breast cancers are categorized clinically as triple-negative breast cancer (TNBC). TNBC is defined by lack of protein expression or over expression of treatment targets such as the Estrogen Receptor α (ER) and Human Epidermal Growth Factor Receptor-2 (HER2), and the prognostic factor PR (Progesterone Receptor). The negative definition of TNBC results in a heterogeneous mix of tumors with variable molecular characteristics and prognosis. Defining TNBC molecular subtypes in detail is of importance to improve prognostication and find new treatment options. Expression of Platelet-derived growth factor-CC (PDGF-CC) has previously been correlated with the TNBC subtype, and paracrine PDGF-CC signaling has been reported to be of importance for maintaining TNBC tumor cell phenotype. We aimed to characterize PDGF-CC expression within the TNBC patient population by combining …

Disclosed is that ER-negative breast cancers can be converted into ER positive breast cancers, such as to a breast cancer of luminal-like phenotype, by treatment with anti-PDGF-CC antibodies. ER-positive breast cancers, including luminal-like breast cancers can be treated with anti-estrogen treatment. On this basis the present disclosure finds that surprisingly, ER-negative breast cancers can be treated with anti-estrogen treatment, if the treatment is combined with treatment with anti-PDGF-CC antibodies. Said treatment may for example be an adjuvant treatment, for example a treatment aiming at reducing the risk of relapse of a breast cancer after removal of the primary tumor by surgery.

The activin-like kinase receptor 1 (ALK1, encoded by ACVRL1) is a member of the transforming growth factor β (TGF-β) superfamily. Expression of ALK1 has been historically associated with endothelial cells, thus serving as a potential target for antiangiogenic therapy in cancer. Despite promising preclinical results with a ligand trap (RAP-041/dalantercept), clinical trials did not show additional benefit of dalantercept when combined or contrasted with the standard of care. This outcome raises the question about patient selection and optimal combination partner in the clinical setting. Moreover, from the biological perspective, how ALK1 signaling shapes the features of a tumor is still largely uncharted. Based on our previous observations, we confirmed that the genetic network correlated with ACVRL1 expression is associated with immune processes in human breast cancer. Next, we validated that inhibition of ALK1 …

Cancer immunotherapy (CIT) has become a standard of care in multiple indications. Apart from radically increasing response rate and prolonging survival, CIT offers the ultimate benefit of any therapy, which is a cure (1).Since the early days of CIT, it was recognized that the benefit is driven by complicated biological mechanisms, which involves a cross-talk between the tumor, its microenvironment, and the overall immune system of the patient (2, 3). Studies aiming to understand and explore CIT mechanisms of action and pharmacodynamic and response prediction biomarkers have initially evaluated each component independently, but ultimately need to look at these questions in concert. Technological advancements in the field combined with the availability of better translational models and ever-expanding clinical datasets enabled basic, translational, and clinical researchers to have a deeper understanding of this complex interaction (4–8).

Developments in sequencing technologies and the sequencing of an ever-increasing number of genomes have revolutionised studies of biodiversity and organismal evolution. This accumulation of data has been paralleled by the creation of numerous public biological databases through which the scientific community can mine the sequences and annotations of genomes, transcriptomes, and proteomes of multiple species. However, to find the appropriate databases and bioinformatic tools for respective inquiries and aims can be challenging. Here, we present a compilation of DNA and protein databases, as well as bioinformatic tools for phylogenetic reconstruction and a wide range of studies on molecular evolution. We provide a protocol for information extraction from biological databases and simple phylogenetic reconstruction using probabilistic and distance methods, facilitating the study of biodiversity and evolution at the molecular level for the broad scientific community.

BackgroundA large component of the tumor microenvironment in breast cancer consists of cancer-associated fibroblasts (CAFs), a cell type which can influence tumor progression, angiogenesis and therapy resistance. Receptors on CAF are activated by ligands secreted from tumor cells resulting in establishment of a malignant paracrine crosstalk, supporting the tumor as a whole. Preclinical data suggests a specific role for tumor cell-secreted Platelet-derived growth factor-CC (PDGF-CC) in maintaining the triple-negative breast cancer (TNBC) phenotype through paracrine activation of PDGFR (Platelet-derived growth factor receptor) on CAFs. Inhibition of CAF PDGFR in preclinical TNBC breast tumor models resulted in tumors converting into a luminal ER subtype, with subsequent response to endocrine therapy. Imatinib, a PDGFR inhibitor, was tested in the preclinical setting leading to comparable results. To …

Dissecting FAP+ mesenchymal cell diversity and regulation uncovers an interferonresponse cancer-associated fibroblast subtype diva-portal.org Digitala Vetenskapliga Arkivet Planned maintenance A system upgrade is planned for 25/10-2023, at 12:00-13:00. During this time DiVA will be unavailable. Simple search Advanced search - Research publications Advanced search - Student thesesStatistics EnglishSvenskaNorsk Change search CiteExport BibTex CSL-JSON CSV 1 CSV 2 CSV 3 CSV 4 CSV 5 CSV all metadata CSV all metadata version 2 RIS Mods MARC-XML ETDMS Link to record Permanent link https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-215328 Direct link https://www.diva-portal.org/smash/record.jsf?pid=diva2:1805678 Cite Citation style apa ieee modern-language-association-8th-edition vancouver Other style More styles Language …

BackgroundExpression of Platelet-derived growth factor-CC (PDGF-CC) is associated with the TNBC (triple-negative breast cancer) subtype. We have previously reported paracrine PDGF-CC signaling to be of importance for maintaining TNBC tumor cell phenotype.MethodsWe aimed to characterize PDGF-CC expression within the TNBC patient population by combining studies of PDGF-CC in tissue microarrays (TMAs) with matching RNA-Seq data and clinical follow-up; all variables originating from the SCAN-B (Sweden Cancerome Analysis Network–Breast) clinical study (NCT02306096). TMAs constructed of primary TNBC patient samples (N= 254) were stained for PDGF-CC using the Dako PT Autostainer system. Tumor cell-specific expression of PDGF-CC intensity was scored as either absent (N= 11), weak (N= 86), intermediate (N= 81) or strong (N= 70).ResultsIntermediate and strong PDGF-CC scores were …

Abstract Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. To elucidate regulatory mechanisms governing the maintenance and propagation of human HSCs ex vivo, we screened libraries of annotated small molecules in human cord blood cells using an optimized assay for detection of functional HSCs during culture. We found that the antifungal agent ciclopirox ethanolamine (CPX) selectively supported immature CD34+CD90+ cells during culture and enhanced their long-term in vivo repopulation capacity. Purified HSCs treated with CPX showed a reduced cell division rate and an enrichment of HSC-specific gene expression patterns. Mechanistically, we found that the HSC stimulating effect of CPX was directly mediated by chelation of the intracellular iron pool, which in turn affected iron-dependent proteins and enzymes mediating …

This article has been corrected: In Figure 4B, the image of MDA-MB-231 cells expressing CSMD1 is an accidental duplicate of the image showing invaded BT-20 cells expressing CSMD1 in Figure 4A. The correct Figure 4, produced using the original data, is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.Original article: Oncotarget. 2016; 7: 76920–76933. https://doi. org/10.18632/oncotarget. 12729

Tumor cells evolve in tumor microenvironment composed of multiple cell types. Among these, endothelial cells (ECs) are the major players in tumor angiogenesis, which is a driver of tumor progression and metastasis. Increasing evidence suggests that ECs also contribute to tumor progression and metastasis as they modify their phenotypes to differentiate into mesenchymal cells through a process known as endothelial-mesenchymal transition (EndoMT). This plasticity of ECs is mediated by various cytokines, including transforming growth factor-β (TGF-β), and modulated by other stimuli depending on the cellular contexts. Recent lines of evidence have shown that EndoMT is involved in various steps of tumor progression, including tumor angiogenesis, intravasation and extravasation of cancer cells, formation of cancer-associated fibroblasts, and cancer therapy resistance. In this review, we summarize current …