Biology subjects

D'Souza-Schorey, C.

Publications and source records attributed to D'Souza-Schorey, C..

4 recordsLinked to original sources

bioRxiv2025

Large extracellular vesicles regulate endothelial angiogenic potential via paracrine and autocrine signaling

Angiogenesis, a process typically associated with tumor growth and development, is often linked to advanced disease and poor clinical outcomes. Tumor cells establish a pro-angiogenic microenvironment through the release of paracrine signaling mediators including extracellular vesicles (EVs). EVs have been shown to facilitate intercellular communication and encompass a diverse range of secreted vesicles, including small EVs (sEVs) which range in size from [~]60 to 100nm and large EVs (L-EVs) which are even more diverse and range from 200nm to >1m in size. Despite advancements in anti-angiogenic cancer therapies, such as bevacizumab, late-stage tumors, including advanced melanomas, exhibit mixed clinical responses. In this study, we elucidate a unique role for melanoma-derived L-EVs in promoting bevacizumab-insensitive endothelial angiogenic phenotypes. This L-EV-mediated increase in endothelial tube formation is sensitive to the effects of sorafenib, a multi-kinase inhibitor, but not SU5416, a selective VEGF-receptor inhibitor. We also demonstrate that melanoma L-EVs contain VEGF as luminal cargo and induce paracrine effects by modulating the endothelial EV secretome. The release from endothelial cells of soluble VEGF, EVs, and pro-angiogenic cytokines such as IL-8, MIF, and PAI-1 drive sustained endothelial tube formation through autocrine signaling. Finally, we show that EV subtypes have distinct effects on the acquisition of angiogenic phenotypes and their roles vary with tumor type. These findings provide new insight into the mechanisms of angiogenic therapy resistance in melanoma and demonstrate the differential functions of EV subtypes in angiogenesis across tumor types.

cancer biology↗

bioRxiv2024

Ancestry-linked stromal variations impact breast epithelial cell invasion

Breast cancer is a significant health challenge worldwide, and disproportionately affects women of African ancestry (AA) who experience higher mortality rates relative to other racial/ethnic groups. Several studies have pointed to biological factors that affect breast cancer outcomes. A recently discovered stromal cell population that expresses PROCR, ZEB1 and PDGFR (PZP cells) was found to be enriched in normal healthy breast tissue from AA donors, and only in tumor adjacent tissues from donors of European ancestry (EA). Here, we investigated the effect of PZP cells on the acquisition of tumorigenic phenotypes in AA and EA human breast epithelial cells to determine its contribution to the biological basis of outcome disparities. Using 3D cell models of tumor invasion, we find that PZP cells confer invasive capacity to epithelial cells independent of genetic ancestry, wherein cells exhibit leader-follower behaviors during extracellular matrix invasion. Enhanced epithelial invasion stems from a combination of AKT activation and fibronectin deposition by the PZP cells. Although activation of AKT in epithelial cells alone is insufficient to induce invasive behaviors, blocking AKT activation markedly reduces invasive capacity. These findings point to the germaneness of differences in breast biology and the multi-faceted roles and enrichment in PZP cells in AA breast tissue, in furthering current understanding of the molecular basis for worse prognosis for patients of African descent.

cancer biology↗

bioRxiv2021

Mechanisms underlying melanoma invasion as a consequence of MLK3 loss

Invasive melanoma is an aggressive form of skin cancer with high incidence of mortality. The process of invasion is a crucial primary step in the metastatic cascade, yet the mechanisms involved are still under investigation. Here we document a critical role for MLK3 (MAP3K11) in the regulation of melanoma cell invasion. We report that cellular loss of MLK3 in melanoma cells promotes cell invasion. Knock down of MLK3 expression results in the hyperactivation of ERK, which is linked to the formation of a BRAF/Hsp90/Cdc37 protein complex. ERK hyperactivation leads to enhanced phosphorylation and inactivation of GSK3{beta} and the stabilization of c-Jun and JNK activity. Blocking of ERK and JNK signaling as well as Hsp90 activity downstream of MLK3-silencing significantly reduces melanoma invasion. Furthermore, our studies show that ERK activation in the aforementioned context is coupled to MT1-MMP transcription as well as the TOM1L1-dependent localization of the membrane protease to invadopodia at the invasive front. These studies provide critical insight into the mechanisms that couple MLK3 loss with BRAF hyperactivation and its consequence on melanoma invasion.

cell biology↗

bioRxiv2019

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

GRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC=\"FIGDIR/small/666750v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (68K):\norg.highwire.dtl.DTLVardef@16dc0c4org.highwire.dtl.DTLVardef@8ab7e2org.highwire.dtl.DTLVardef@12e5acforg.highwire.dtl.DTLVardef@4bf298_HPS_FORMAT_FIGEXP M_FIG C_FIG SUMMARYBreast cancer brain metastases (BCBM) have a 5-20 year latency and account for up to 30% of mortality. Developing new therapeutics requires a molecular understanding of adaptation to the brain microenvironment. Here, we combined RNA-sequencing of BCBM development with a reverse genetic screen in Drosophila melanogaster and identified Rab11b, an endosomal recycling protein, as a mediator of metastatic adaptation. We show that disseminated cells up-regulate Rab11b early after arrival in the brain, allowing control of the cell surface proteome through recycling of proteins required for successful interaction with the microenvironment, including integrin {beta}1. Rab11b-mediated control of integrin {beta}1 surface expression allows ligation to the brain ECM, activating mechanotransduction signaling to allow survival and proliferation. We propose a model in which up-regulation of Rab11b allows disseminated cells to recycle needed proteins during metastatic adaptation, without strictly requiring transcription and translation, to allow for metastatic outgrowth.\n\nManuscript SummaryRab11b up-regulation in the brain microenvironment promotes recycling of cargo proteins required for breast cancer brain metastasis, including increased surface expression of integrin {beta}1, which allows brain extracellular matrix attachment and mechanotransduction. Inhibition of the mevalonate pathway with statins prevents geranylgeranylation of Rab11b, decreasing cargo recycling, and inhibiting brain metastasis.

cancer biology↗