Biology subjects

Hartiala, P.

Publications and source records attributed to Hartiala, P..

5 recordsLinked to original sources

bioRxiv2026

Single-Cell Profiling Reveals Innate Lymphoid Cells and OX40 Activation in Breast Cancer-Related Lymphedema

ABSTRACT Breast cancer-related lymphedema (BCRL) is a severe complication affecting up to 40% of breast cancer survivors. Stage II or chronic disease stages are characterized by upper-limb edema, fibrotic adipose tissue accumulation, pain, and recurrent infections. Despite its clinical burden, BCRL lacks effective pharmacological therapies and the molecular mechanisms driving disease progression remain poorly understood. To better define the regulatory mechanisms underlying chronic BCRL, we performed transcriptomic and quantitative analyses of stromal vascular fraction cells (SVF or non-adipose cell fraction) in BCRL-derived subcutaneous adipose tissue. CD45+ immune cells from stage II BCRL were compared with those from healthy lean and obese adipose tissue controls. Although our analyses identified multiple leukocyte populations, we focused primarily on innate lymphoid cells (ILCs), particularly ILC2 and ILC3 subsets, which were more abundant and active in BCRL tissues. Bioinformatics analysis of cell-cell communication positioned ILCs as central immune-regulatory hubs in BCRL through inflammatory and tissue-remodeling pathways, including connections to IL2, OX40, KIT, and LT signaling. Strong bidirectional communication between ILCs and regulatory T cells via OX40 signaling was uniquely detected in BCRL. Consistent with these findings, protein-based analyses confirmed increased inflammatory mediators and enrichment of the OX40 and OX40L co-stimulatory pair in BCRL tissues. Taken together, our findings identify OX40-dependent ILC-signaling as a novel regulatory program supporting chronic inflammation and pathological tissue remodeling in BCRL.

immunology↗

bioRxiv2026

Filopodia-mediated trans-endocytosis

Cell-cell communication in tissues is influenced by contact geometry and molecular signalling. Here, we demonstrate that epithelial intercellular filopodia can penetrate neighbouring cells to form micrometre-long, double-membrane "impact sites" and, in some instances, initiate trans-endocytosis. Using super-resolution live imaging and three-dimensional electron microscopy in cell models, xenografts, and patient-derived tissues, we observe widespread intercellular filopodia and extensive interdigitation at the cell-cell interface. Filopodia impact sites in the recipient cell recruit PACSIN2 into dynamic "PACSIN2 fingers" and are specifically enriched for caveolin-1 and dynamin-2, while clathrin and CLIC pathway markers are not enriched. Most contacts are transient and resolved by retraction, but some undergo scission, with recipient cells internalising filopodial tips across both homotypic and heterotypic interactions, including cancer-endothelium contacts. Correlative light and FIB-SEM analysis reveals that internalised tips are often double-membraned, closely associated with endoplasmic reticulum tubules, and can traffic to lysosomes. These findings define a protrusion-driven, curvature-dependent uptake pathway at cell-cell interfaces and identify filopodia as exchange organelles in epithelial collectives.

cell biology↗

bioRxiv2024

Dynamic HSF2 regulation drives breast cancer progression by steering the balance between proliferation and invasion

Phenotypic plasticity is a hallmark of breast carcinogenesis that facilitates the acquisition of invasive properties via epithelial-mesenchymal transition (EMT). Transforming growth factor-beta (TGF-{beta}), a key EMT-inducing cytokine, drives pro-metastatic gene programs through downstream transcription factors. Among mammalian stress-protective transcription factors, heat shock factor 2 (HSF2) has been associated with cancer progression, but the mechanisms regulating HSF2 expression and activity are unknown. Here, we demonstrate that TGF-{beta} stimulation downregulates HSF2 to enable activation of an invasive phenotype. Remarkably, ectopic expression of HSF2 in breast cancer cells inhibited TGF-{beta}-mediated effects on gene expression and cellular properties. By using both in vitro cell models and in vivo zebrafish xenografts, we found that a temporal downregulation of HSF2 is a prerequisite for EMT activation, while ectopically sustained HSF2 promotes rapid cell proliferation and survival. Analyses of human patient tissues corroborated our results by showing that HSF2 is dynamically regulated during breast cancer progression. Specifically, HSF2 expression and nuclear co-localization with the proliferation marker Ki67 are dramatically increased already in ductal carcinoma in situ. Altogether, our findings expand the pathological landscape of HSF2, demonstrating that dynamic regulation of HSF2 is an inherent property of malignant progression and characterizes the distinct stages of breast cancer.

cell biology↗

bioRxiv2023

Morphometric analysis of the terminal ductal lobular unit architecture in human breast

AbstractThe major lactiferous ducts of the human breast branch out and ultimately end at terminal ductal lobular units (TDLUs). These glandular structures are the source of milk upon lactation, and also the most common origin of breast cancer. Despite their functional and clinical importance, the three dimensional (3D) architecture of TDLUs has remained undetermined, largely due to their absence in rodent animal models. By utilizing recent technological advances in optical tissue clearing, 3D reconstruction histology and microscopy, we imaged the 3D structure of healthy human breast tissue to determine whether general branching patterns or cell type specific niches exist in the TDLU. Our data demonstrate that highly branched TDLUs, also exhibiting elevated proliferation, are uncommon in the breast tissue regardless of donor age, parity or hormonal contraception. Overall, TDLUs have a consistent shape and their branch parameters are largely comparable between different TDLUs and individuals irrespective of donor age or parity. Simulation of TDLU branching morphogenesis in 3D by mathematical modelling suggests that evolutionarily conserved mechanisms regulate mammary gland branching in humans and mice, despite their anatomical differences. The data also demonstrate a new level of organization within the TDLU structure identifying a main subtree that dominates in bifurcation events and exhibits a more duct-like keratin expression pattern. In all, our data provide the first structural insights into 3D human breast anatomy and branching, and exemplify the power of volumetric imaging in deeper understanding of human breast biology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/532249v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@16caf77org.highwire.dtl.DTLVardef@73d65dorg.highwire.dtl.DTLVardef@fea93eorg.highwire.dtl.DTLVardef@1192c1c_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2021

Myosin-X-dependent assembly of the extracellular matrix limits breast cancer invasion

Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer, where the tumor is encapsulated by a basement membrane (BM). At the invasive phase, the BM barrier is compromised enabling tumor cells to escape into the surrounding stroma. The molecular mechanisms that establish and maintain an epithelial BM barrier in vivo are poorly understood. Myosin-X (MYO10) is a filopodia-inducing motor protein implicated in metastasis and poor clinical outcome in patients with invasive breast cancer (IBC). We compared MYO10 expression in patient-matched normal breast tissue and DCIS lesions and found elevated MYO10 expression in DCIS samples, suggesting that MYO10 might facilitate the transition from DCIS to IBC. Indeed, MYO10 promoted the formation of filopodia and cell invasion in vitro and positively regulated the dissemination of individual cancer cells from IBC lesions in vivo. However, MYO10-depleted DCIS xenografts were, unexpectedly, more invasive. In these xenografts, MYO10 depletion compromised BM formation around the lesions resulting in poorly defined tumor borders and increased cancer cell dispersal into the surrounding stroma. Moreover, MYO10-depleted tumors showed increased EMT-marker-positive cells, specifically at the tumor periphery. We also observed cancer spheroids undergoing rotational motion and recruiting BM components in a filopodia-dependent manner to generate a near-continuous extracellular matrix boundary. Taken together, our data identify a protective role for MYO10 in early-stage breast cancer, where MYO10-dependent tumor cell protrusions support BM assembly at the tumor-stroma interface to limit cancer progression, and a pro-invasive role that facilitates cancer cell dissemination at later stages. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/464987v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d90a4eorg.highwire.dtl.DTLVardef@133ba9borg.highwire.dtl.DTLVardef@1204a05org.highwire.dtl.DTLVardef@dba254_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- Filopodia sculpt the tumor-proximal stroma in pre-invasive ductal carcinoma in situ (DCIS). - Filopodia-dependent basement membrane (BM) assembly limits invasive transition of DCIS-like tumors in vivo. - Loss of MYO10-dependent filopodia impairs BM assembly and induces an EMT-like phenotype at the tumor-stroma interface in vivo. - MYO10 filopodia are anti-invasive in DCIS but facilitate dissemination in invasive breast cancer.

cell biology↗