Biology subjects

Bostrom, P.

Publications and source records attributed to Bostrom, P..

3 recordsLinked to original sources

bioRxiv2024

Breast Cancer Remodels Lymphatics in Sentinel Lymph Nodes

Cancer metastasis to sentinel lymph nodes (LNs) is often the first marker of potential disease progression. Although it is recognized that tumor-induced lymphangiogenesis facilitates metastasis into LNs in murine models, tumor-induced alterations in human lymphatic vessels remain obscure. We used single-cell RNA sequencing to profile lymphatic endothelial cell (LEC) subsets in paired metastatic and non-metastatic LNs obtained from patients with treatment-naive breast cancer. Tumor metastasis decreases immunoregulatory LEC subsets, such as PD-L1+ subcapsular sinus LECs, while inducing an increase in capillary-like CD200+ HEY1+ LECs. Matrix Gla protein (MGP) was the most upregulated gene in metastatic LN LECs, and its expression on LECs was TGF-{beta} and VEGF dependent. Upregulated MGP promotes cancer cell adhesion to LN lymphatics. Thus, breast cancer cell metastasis to LNs remodels LEC subsets in human LNs and escalates MGP expression, potentially facilitating cancer cell dissemination through the lymphatic system.

immunology↗

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↗

bioRxiv2018

SORLA-driven endosomal trafficking regulates the oncogenic fitness of HER2

Human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. Endosomal trafficking of many other receptor tyrosine kinases regulates their oncogenic signaling, but the prevailing view is that HER2 is retained on the cell surface. Here we reveal that in cancer cells Sortilin related receptor 1 (SORLA; SORL1) forms a complex with HER2 and regulates its subcellular distribution by promoting recycling of endosomal HER2 back to plasma membrane. Expression of SORLA in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA targets HER2 to late endosomal/lysosomal compartments, impairs HER2-driven signaling and in vivo tumor growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

cell biology↗