Biology subjects

Sathe, M.

Publications and source records attributed to Sathe, M..

4 recordsLinked to original sources

bioRxiv2026

MNRR1 is required for Triple Negative Breast Cancer growth and metastasis and can be targeted by repurposed drugs.

Despite progress in recent decades, breast cancers remain the most diagnosed malignancies, and second leading cause of cancer death, in women. Although improved screening and systemic and endocrine adjuvant approaches have contributed to major declines in breast cancer mortality, current standard of care drugs are extremely toxic, and many women continue to be overtreated. Although nearly two-thirds of breast cancers are hormone-responsive, aggressive subtypes, particularly Triple Negative Breast Cancer (TNBC), still lack safe oral medications. Recently the roles that mitochondria play in TNBC carcinogenesis, metastasis, and resistance to treatment have garnered a great deal of attention. Contrary to the popular dogma that cancer cells are powered by glycolysis, metastatic breast cancer cells have enhanced mitochondrial function. Our work identified that Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22), a key coordinator of mitochondrial-nuclear crosstalk that is physically present in both compartments, is overexpressed in TNBC cells and is an important regulator of metastasis signaling. We have identified Heat Shock Factor 1 (HSF1) as the main transcription factor that activates the MNRR1 promoter in TNBC cell lines. In the mitochondria, MNRR1 protein facilitates ATP production and inhibits apoptosis, whereas in the nucleus it regulates the transcription of stress-responsive genes including several required for epithelial to mesenchymal transition (EMT), metabolic flexibility, and cell growth. Thus, each of the bi-organellar functions of MNRR1 constitutes processes regarded as hallmarks of cancer. For reasons that are not yet fully understood, MNRR1 levels display a significant and robust ancestry bias, showing increased expression in tumor samples from Non-Hispanic Black (NHB) women when compared to disease-matched tumors from Non-Hispanic White (NHW) patients. It is possible that increased levels of MNRR1 may underlie the aggressive metastatic phenotype observed in many NHB patients. In further support of this observation, loss of MNRR1 function, either genetically or by use of inhibitors, reduces TNBC growth and metastasis. MNRR1 therefore is an attractive therapeutic target that could be exploited for design of novel therapies or as adjuncts to existing ones.

cancer biology↗

bioRxiv2022

Post-injury hydraulic fracturing drives fissure formation in the zebrafish basal epidermal cell layer

The skin epithelium acts as the barrier between an organisms internal and external environments. In zebrafish and other freshwater organisms, this barrier function requires withstanding a large osmotic pressure differential. Wounds breach this epithelium, causing a large disruption to the tissue microenvironment due to the mixing of isotonic interstitial fluid with the external hypotonic fresh water. Here we show that, following acute injury, the larval zebrafish epidermis undergoes a dramatic fissuring process that resembles hydraulic fracturing, driven by the influx of external fluid. The fissuring starts in the basal epidermal layer nearest to the wound, and then propagates at a constant rate through the tissue spanning over one hundred micrometers; during this process the outermost superficial epidermal layer remains intact. Fissuring is completely inhibited when larvae are wounded in an isotonic external media, suggesting that osmotic pressure gradients drive fissure. Additionally, fissuring partially depends on myosin II activity, as its inhibition reduces fissure propagation away from the wound. During and after fissuring, the basal layer forms large macropinosomes (with cross-sectional areas ranging from 1-10 {micro}m2), presumably to clear the excess fluid. We conclude that excess external fluid entry through the wound and subsequent closure of the wound through actomyosin purse string contraction in the superficial cell layer causes fluid pressure buildup in the extracellular space of the zebrafish epidermis. This excess fluid pressure causes tissue to fissure, and eventually the fluid is cleared through macropinocytosis.

cell biology↗

bioRxiv2022

Listeria monocytogenes Co-opts Caveolin-Mediated E-cadherin Trafficking and Macropinocytosis for Epithelial Cell-to-Cell Spread

Listeria monocytogenes is an intracellular bacterial pathogen that spreads directly between adjacent host cells without exposure to the extracellular space. Recent studies have identified several host cell factors that promote L. monocytogenes cell-to-cell spread in epithelial monolayers, but details of the mechanism remain unclear. We find that the adherens junction protein, E-cadherin, promotes L. monocytogenes cell-to-cell spread at the recipient side of cell contacts. In particular, two point mutations in E-cadherins cytoplasmic domain that prevent its ubiquitination hinder bacterial cell-to-cell spread efficiency without reducing the extent of contact between neighboring cells. As ubiquitination induces E-cadherin endocytosis, we hypothesize that E-cadherin promotes protrusion engulfment, where donor cell protrusions containing L. monocytogenes are taken up by the recipient cell concurrently with E-cadherin internalization. In support of this hypothesis, we show that inhibiting caveolin-mediated membrane trafficking reduces L. monocytogenes cell-to-cell spread only under conditions where E-cadherin can be ubiquitinated. Additionally, we demonstrate that macropinocytosis also contributes to dissemination of L. monocytogenes through an epithelial monolayer.

microbiology↗

bioRxiv2017

Small GTPases and BAR domain proteins regulate branched actin to make clathrin and dynamin independent endocytic vesicles

Numerous endocytic pathways operate simultaneously at the cell surface. Here we focus on the molecular machinery involved in the generation of endocytic vesicles of the clathrin and dynamin-independent CLIC/GEEC (CG) pathway. This pathway internalises many GPI-anchored proteins and a large fraction of the fluid-phase in different cell types. We developed a real-time TIRF assay using pH-sensitive GFP-GPI to identify nascent CG endocytic sites. The temporal profile of known CG pathway modulators showed that ARF1/GBF1 (GTPase/GEF pair) and CDC42 (RhoGTPase) are recruited sequentially to CG endocytic sites, [~]60s and [~]9s prior to scission. Using a limited RNAi screen, we found several BAR domain proteins affecting CG endocytosis and focused on IRSp53 and PICK1 that have interactions with CDC42 and ARF1 respectively. IRSp53, an I-BAR domain containing protein, was recruited to the plasma membrane at the site of forming CG endocytic vesicles and in its absence, nascent endocytic CLICs, did not form. The requirement for actin polymerization in the CG pathway suggested a role for nucleators of actin polymerization, and ARP2/3 was found enriched at the site of the forming endocytic vesicle. PICK1, a BAR domain containing protein and the ARP2/3 inhibitor is recruited at an early stage along with ARP2/3, but is removed from the endocytic site coincident with CDC42 recruitment and a burst of Factin polymerization. This study provides a spatio-temporal understanding of the molecular machinery necessary to build a CG endocytic vesicle.

cell biology↗