Biology subjects

Borges, H.

Publications and source records attributed to Borges, H..

3 recordsLinked to original sources

bioRxiv2023

Age and obesity-driven changes in the extracellular matrix of the primary tumor and metastatic site influence tumor invasion and metastatic outgrowth

Younger age and obesity increase the incidence and metastasis of triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. The extracellular matrix (ECM) promotes tumor invasion and metastasis. We characterized the effect of age and obesity on the ECM of mammary fat pads, lungs, and liver using a diet-induced obesity (DIO) model. At 4 week intervals, we either injected the mammary fat pads with allograft tumor cells to characterize tumor growth and metastasis or isolated the mammary fat pads and livers to characterize the ECM. Age had no effect on tumor growth but increased lung and liver metastasis after 16 weeks. Obesity increased tumor growth starting at 12 weeks, increased liver metastasis only at 4 weeks, and weight gain correlated to increased lung but not liver metastasis. Utilizing whole decellularized ECM coupled with proteomics, we found that early stages of obesity were sufficient to induce changes in the ECM composition and invasive potential of mammary fat pads with increased abundance of pro-invasive ECM proteins Collagen IV and Collagen VI. We identified cells of stromal vascular fraction and adipose stem and progenitor cells as primarily responsible for secreting Collagen IV and VI, not adipocytes. We characterized the changes in ECM in the lungs and liver, and determined that older age decreases the metastatic potential of lung and liver ECM while later-stage obesity increases the metastatic potential. These data implicate ECM changes in the primary tumor and metastatic microenvironment as mechanisms by which age and obesity contribute to breast cancer progression. SignificanceYounger age and obesity increase the incidence and metastasis of triple-negative breast cancer. Our data suggest that changes in the breast, lung and liver ECM are driving some of these effects.

cancer biology↗

bioRxiv2023

Cell morphology best predicts tumorigenicity and metastasis in vivo across multiple TNBC cell lines of different metastatic potential

BackgroundMetastasis is the leading cause of death in breast cancer patients. For metastasis to occur, tumor cells must invade locally, intravasate, and colonize distant tissues and organs, all steps that require tumor cell migration. The majority of studies on invasion and metastasis rely on human breast cancer cell lines. While it is known that these cells have different properties and abilities for growth and metastasis, the in vitro morphological, proliferative, migratory, and invasive behavior of these cell lines and their correlation to in vivo behavior is poorly understood. Thus, we sought to classify each cell line as poorly or highly metastatic by characterizing tumor growth and metastasis in a murine model of six commonly used human triple-negative breast cancer xenografts, as well as determine which in vitro assays commonly used to study cell motility best predict in vivo metastasis. MethodsWe evaluated the liver and lung metastasis of human TNBC cell lines MDA-MB-231, MDA-MB-468, BT549, Hs578T, BT20, and SUM159 in immunocompromised mice. We characterized each cell lines cell morphology, proliferation, and motility in 2D and 3D to determine the variation in these parameters between cell lines. ResultsWe identified MDA-MB-231, MDA-MB-468, and BT549 cells as highly tumorigenic and metastatic, Hs578T as poorly tumorigenic and metastatic, BT20 as intermediate tumorigenic with poor metastasis to the lungs but highly metastatic to the livers, and SUM159 as intermediate tumorigenic but poorly metastatic to the lungs and livers. We showed that metrics that characterize cell morphology are the most predictive of tumor growth and metastatic potential to the lungs and liver. Further, we found that no single in vitro motility assay in 2D or 3D significantly correlated with metastasis in vivo. ConclusionsOur results provide an important resource for the TNBC research community, identifying the metastatic potential of 6 commonly used cell lines. Our findings also support the use of cell morphological analysis to investigate the metastatic potential and emphasize the need for multiple in vitro motility metrics using multiple cell lines to represent the heterogeneity of metastasis in vivo.

cancer biology↗

bioRxiv2020

Spatiotemporal dynamics between interictal epileptiform discharges and ripples during associative memory processing

We describe the spatiotemporal course of cortical high-gamma activity (HGA), hippocampal ripple activity and interictal epileptiform discharges (IEDs) during an associative memory task in 15 epilepsy patients undergoing invasive electroencephalography. Successful encoding trials manifested significantly greater HGA in hippocampus and frontal regions. Successful cued recall trials manifested sustained HGA in hippocampus compared to failed responses. Hippocampal ripple rates were greater during successful encoding and retrieval trials. IEDs during encoding were associated with 15% decreased odds of remembering in hippocampus (95% CI 6-23%). Hippocampal IEDs during retrieval predicted 25% decreased odds of remembering (15-33%). Odds of remembering were reduced by 25-52% if IEDs occurred during the 500-2000 ms window of encoding or by 41% during retrieval. During encoding and retrieval, hippocampal IEDs were followed by a transient decrease in ripple rate. We hypothesize that IEDs impair associative memory in a regionally and temporally specific manner by decreasing physiologic hippocampal ripples necessary for effective encoding and recall. Because dynamic memory impairment arises from pathological IED events competing with physiological ripples, IEDs represent a promising therapeutic target for memory remediation in patients with epilepsy. SummaryHippocampal interictal epileptiform discharges in hippocampus acutely impair declarative memory, potentially by hijacking physiological processes essential for encoding and recall.

neuroscience↗