A5039002989- Cancer Cells and Metastasis
- Cancer, Hypoxia, and Metabolism
- Cancer Genomics and Diagnostics
- Dietary Effects on Health
- Cancer-related Molecular Pathways
- Diet and metabolism studies
- Pancreatic function and diabetes
- Microtubule and mitosis dynamics
- Cancer Research and Treatments
- Single-cell and spatial transcriptomics
- Cancer Immunotherapy and Biomarkers
- Hydrogen's biological and therapeutic effects
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Metabolism, Diabetes, and Cancer
- RNA modifications and cancer
- Radiopharmaceutical Chemistry and Applications
- Diabetes Treatment and Management
- Bone and Dental Protein Studies
- FOXO transcription factor regulation
- Diabetes Management and Research
- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- Immune cells in cancer
- Cell Image Analysis Techniques
The University of Texas MD Anderson Cancer Center
2015-2024
Lexicon Pharmaceuticals (United States)
2010-2019
Resistance to neoadjuvant chemotherapy in triple-negative breast cancer can be mediated by a reversible chemotherapy-tolerant state.
Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion Ksr2 leads to obesity mice, suggesting a role energy homeostasis. We explored the KSR2 humans by sequencing 2,101 individuals with severe early-onset and 1,536 controls. identified rare variants that disrupt through Raf-MEK-ERK pathway impair cellular fatty acid oxidation glucose transfected cells; effects can be ameliorated commonly prescribed antidiabetic...
Sodium-glucose cotransporter 2 (SGLT2) is the major, and SGLT1 minor, transporter responsible for renal glucose reabsorption. Increasing urinary excretion (UGE) by selectively inhibiting SGLT2 improves glycemic control in diabetic patients. We generated Sglt1 Sglt2 knockout (KO) mice, Sglt1/Sglt2 double-KO (DKO) wild-type (WT) littermates to study their relative determine contributions of UGE. Relative WTs, KOs had improved oral tolerance were resistant streptozotocin-induced diabetes. fed...
The FAM20 family of secreted proteins consists three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for in modulating biomineralization processes. authors report here findings knockout mice having null mutations affecting each the proteins. Both Fam20a Fam20c survived adulthood showed defects. Fam20b –/– embryos severe stunting increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification...
Abstract Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intra-tumoral heterogeneity (ITH), but how ITH contributes to metastasis is unclear. Here, clonal dynamics during were studied in vivo using two patient-derived xenograft (PDX) models established from the treatment-naive primary tumors TNBC patients diagnosed synchronous metastasis. Genomic sequencing and high-complexity barcode-mediated tracking reveal robust alterations architecture...
Significance Cancer patients undergoing chemotherapy experience high rates of dose-limiting morbidity. Recently, short-term fasting prior to was shown decrease toxicity. Herein we report that protects multiple small intestinal stem cell populations marked by Lgr5 , Bmi1 or HopX expression and maintains barrier function preserve architecture from lethal DNA damage. Our findings provide insight into how the host toxicity associated with high-dose chemotherapy.
The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies highly effective at reducing vertebral but not fractures. Cortical bone is a major determinant of strength. To identify novel drug targets, we phenotyped cortical 3 366 viable mouse strains with global knockouts druggable genes. thickness was substantially elevated in Notum-/- mice. NOTUM secreted WNT lipase observed high expression osteoblasts osteoclasts. Three...
Abstract Tumor cells disseminate early in tumor development making metastasis-prevention strategies difficult. Identifying proteins that promote the outgrowth of disseminated may provide opportunities for novel therapeutic strategies. Despite multiple studies demonstrating mesenchymal-to-epithelial transition (MET) is critical metastatic colonization, key regulators initiate this remain unknown. We serially passaged lung metastases from a primary triple negative breast cancer xenograft to...
β-hydroxybutyrate (β-OHB) is an essential metabolic energy source during fasting and functions as a chromatin regulator by lysine β-hydroxybutyrylation (Kbhb) modification of the core histones H3 H4. We report that Kbhb on histone (H3K9bhb) enriched at proximal promoters critical gene subsets associated with lipolytic ketogenic pathways in small intestine (SI) crypts fasting. Similar enrichment observed Lgr5+ stem cell-enriched epithelial spheroids treated β-OHB vitro. Combinatorial state...
The kinase suppressor of ras 2 (KSR2) gene resides at human chromosome 12q24, a region linked to obesity and type diabetes (T2D). While knocking out phenotypically screening mouse orthologs thousands druggable genes, we found KSR2 knockout (KSR2(-/-)) mice be more obese glucose intolerant than melanocortin 4 receptor(-/-) (MC4R(-/-)) mice. T2D KSR2(-/-) resulted from hyperphagia which was unresponsive leptin did not originate downstream MC4R. kinases AMP-activated protein (AMPK) mammalian...
Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half these cancers respond to the drug. Enhancing response with paclitaxel could improve outcomes women both diseases.Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple cancer cell lines determine whether they sensitivity Sulforhodamine B assays. The effects 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on...
LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated effect of orally administered on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower plasma total glucagon-like peptide-1 (GLP-1) levels higher an challenge; these decreased persisted even when challenge occurred 15 hours dosing ad lib-fed mice. Further, treating...
Abstract Triple negative breast cancer (TNBC) accounts for 15–20% of cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is current standard care patients early-stage TNBC. However, up to 70% TNBC have significant residual disease once NACT completed, which associated a high risk developing recurrence within two three years surgical resection. To identify targetable vulnerabilities chemoresistant TNBC, we generated longitudinal patient-derived...
Oral agents are needed that improve glycemic control without increasing hypoglycemic events in patients with type 1 diabetes (T1D). Sotagliflozin may meet this need, because compound lowers blood glucose through the insulin-independent mechanisms of inhibiting kidney SGLT2 and intestinal SGLT1. We examined effect sotagliflozin on rate hypoglycemia measurements T1D mice maintained a low daily insulin dose, compared these results to those from better higher dose alone.Nonobese diabetes-prone...
Abstract There is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied a mouse model cancer reveals that the tumor niche characterized by expanded basal-like population, specialization subpopulations, mixed-lineage cells potentially serving transition state between luminal basal phenotypes. Despite vast cell-intrinsic differences, are functionally indistinguishable once...
Abstract Chemotherapy, along with the PD1 inhibitor pembrolizumab, is recommended standard of care for patients primary triple negative breast cancer (TNBC). Nearly half TNBC treated neoadjuvant chemotherapy (NACT) have excellent responses. However, those significant residual burden (RCB) after NACT are at high risk recurrence or metastatic relapse within two years. Due to challenges posed by inter- and intratumoral heterogeneity TNBC, it critical develop appropriate models predicting...
Abstract Normal tissue toxicity often restricts the administration of effective radiation doses for optimal tumor cell elimination. We identified a novel host-protective effect conferred by short-term fasting when treating mice with high dose radiation. showed that 24h induces epigenetic and transcriptional changes in small intestinal epithelial cells (siECs) confers protection to stem from Here we report gut microbiome favoring bacteria producing metabolites, specifically short-chain fatty...
SUMMARY Triple negative breast cancer (TNBC) that fails to respond neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies eradicate chemoresistant disease requires experimental models recapitulate the heterogeneity characteristic of TNBC. To end, we established a biobank 92 orthotopic patient-derived xenograft (PDX) TNBC from tumors 75 patients enrolled in ARTEMIS clinical trial ( NCT02276443 ) at MD Anderson Cancer Center, including 12 longitudinal sets generated...
β-hydroxybutyrate (β-OHB) provides an essential metabolic energy source during fasting and functions as epigenetic regulator by lysine β-hydroxybutyrylation (Kbhb) modification of core histones H3 H4. We report that H3K9bhb, but not H4K12bhb, becomes highly enriched at proximal promoters genes regulating lipolytic ketogenic programs in small intestinal (SI) crypts these pathways are transcriptionally activated Lgr5 + SI stem cells. Similar Kbhb enrichment is observed cell-enriched epithelial...
Abstract Short-term fasting in mice has been shown to increase survival from lethal doses of chemotherapy; however, the route protection these animals is unknown. In this study we demonstrate that prior chemotherapy protects small intestinal (SI) stem cells exposed high dose etoposide. Histologic and vitro crypt culture analyses show nearly all SI were lost when fed treated with etoposide but numbers survived fasted similarly treated. etoposide, multiple cell populations marked by Lgr5, Bmi1...
<p>Supplementary Data and Methods</p>
<p>Supplementary Data and Methods</p>