Publications by authors named "Raghu Kalluri"

250 Publications

Unique somatic variants in DNA from urine exosomes of individuals with bladder cancer.

Mol Ther Methods Clin Dev 2021 Sep 29;22:360-376. Epub 2021 May 29.

Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Bladder cancer (BC), a heterogeneous disease characterized by high recurrence rates, is diagnosed and monitored by cystoscopy. Accurate clinical staging based on biopsy remains a challenge, and additional, objective diagnostic tools are needed urgently. We used exosomal DNA (exoDNA) as an analyte to examine cancer-associated mutations and compared the diagnostic utility of exoDNA from urine and serum of individuals with BC. In contrast to urine exosomes from healthy individuals, urine exosomes from individuals with BC contained significant amounts of DNA. Whole-exome sequencing of DNA from matched urine and serum exosomes, bladder tumors, and normal tissue (peripheral blood mononuclear cells) identified exonic and 3' UTR variants in frequently mutated genes in BC, detectable in urine exoDNA and matched tumor samples. Further analyses identified somatic variants in driver genes, unique to urine exoDNA, possibly because of the inherent intra-tumoral heterogeneity of BC, which is not fully represented in random small biopsies. Multiple variants were also found in untranslated portions of the genome, such as microRNA (miRNA)-binding regions of the gene. Gene network analyses revealed that exoDNA is associated with cancer, inflammation, and immunity in BC exosomes. Our findings show utility of exoDNA as an objective, non-invasive strategy to identify novel biomarkers and targets for BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtm.2021.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408559PMC
September 2021

Clinical and therapeutic relevance of cancer-associated fibroblasts.

Nat Rev Clin Oncol 2021 Dec 6;18(12):792-804. Epub 2021 Sep 6.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer progression through complex interactions with other cell types in the tumour microenvironment. As well as generating extracellular matrix components that contribute to the structure and function of the tumour stroma, CAFs undergo epigenetic changes to produce secreted factors, exosomes and metabolites that influence tumour angiogenesis, immunology and metabolism. Because of their putative pro-oncogenic functions, CAFs have long been considered an attractive therapeutic target; however, clinical trials of treatment strategies targeting CAFs have mostly ended in failure and, in some cases, accelerated cancer progression and resulted in inferior survival outcomes. Importantly, CAFs are heterogeneous cells and their characteristics and interactions with other cell types might change dynamically as cancers evolve. Studies involving single-cell RNA sequencing and novel mouse models have increased our understanding of CAF diversity, although the context-dependent roles of different CAF populations and their interchangeable plasticity remain largely unknown. Comprehensive characterization of the tumour-promoting and tumour-restraining activities of CAF subtypes, including how these complex bimodal functions evolve and are subjugated by neoplastic cells during cancer progression, might facilitate the development of novel diagnostic and therapeutic approaches. In this Review, the clinical relevance of CAFs is summarized with an emphasis on their value as prognosis factors and therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41571-021-00546-5DOI Listing
December 2021

Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic Kras in pancreatic cancer.

Life Sci Alliance 2021 09 19;4(9). Epub 2021 Jul 19.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA

CRISPR/Cas9 is a promising technology for gene editing. To date, intracellular delivery vehicles for CRISPR/Cas9 are limited by issues of immunogenicity, restricted packaging capacity, and low tolerance. Here, we report an alternative, nonviral delivery system for CRISPR/Cas9 based on engineered exosomes. We show that non-autologous exosomes can encapsulate CRISPR/Cas9 plasmid DNA via commonly available transfection reagents and can be delivered to recipient cancer cells to induce targeted gene deletion. As a proof-of-principle, we demonstrate that exosomes loaded with CRISPR/Cas9 can target the mutant oncogenic allele in pancreatic cancer cells to suppress proliferation and inhibit tumor growth in syngeneic subcutaneous and orthotopic models of pancreatic cancer. Exosomes may thus be a promising delivery platform for CRISPR/Cas9 gene editing for targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.26508/lsa.202000875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321670PMC
September 2021

Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine.

Nat Commun 2021 07 9;12(1):4228. Epub 2021 Jul 9.

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-24240-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270912PMC
July 2021

Quantitative proteomics identifies the core proteome of exosomes with syntenin-1 as the highest abundant protein and a putative universal biomarker.

Nat Cell Biol 2021 06 9;23(6):631-641. Epub 2021 Jun 9.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Exosomes are extracellular vesicles derived from the endosomal compartment that are potentially involved in intercellular communication. Here, we found that frequently used biomarkers of exosomes are heterogeneous, and do not exhibit universal utility across different cell types. To uncover ubiquitous and abundant proteins, we used an unbiased and quantitative proteomic approach based on super-stable isotope labeling with amino acids in cell culture (super-SILAC), coupled to high-resolution mass spectrometry. In total, 1,212 proteins were quantified in the proteome of exosomes, irrespective of the cellular source or isolation method. A cohort of 22 proteins was universally enriched. Fifteen proteins were consistently depleted in the proteome of exosomes compared to cells. Among the enriched proteins, we identified biogenesis-related proteins, GTPases and membrane proteins, such as CD47 and ITGB1. The cohort of depleted proteins in exosomes was predominantly composed of nuclear proteins. We identified syntenin-1 as a consistently abundant protein in exosomes from different cellular origins. Syntenin-1 is also present in exosomes across different species and biofluids, highlighting its potential use as a putative universal biomarker of exosomes. Our study provides a comprehensive quantitative atlas of core proteins ubiquitous to exosomes that can serve as a resource for the scientific community.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41556-021-00693-yDOI Listing
June 2021

αSMA fibroblasts suppress Lgr5 cancer stem cells and restrain colorectal cancer progression.

Oncogene 2021 Jul 9;40(26):4440-4452. Epub 2021 Jun 9.

Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The development and progression of solid tumors is dependent on cancer cell autonomous drivers and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) in the TME possess both tumor-promoting and tumor-restraining functions. In the current study, we interrogated the role of αSMA CAFs in a genetic mouse model of metastatic colorectal cancer (CRC). Selective depletion of αSMA CAFs resulted in increased tumor invasiveness, lymph node metastasis, and reduced overall survival. Depletion of αSMA CAFs reduced BMP4 and increased TGFβ1 secretion from stromal cells, and was associated with increased Lgr5 cancer stem-like cells (CSCs) and the generation of an immunosuppressive TME with increased frequency of Foxp3 regulatory T cells and suppression of CD8 T cells. This study demonstrates that αSMA CAFs in CRC exert tumor-restraining functions via BMP4/TGFβ1 paracrine signaling that serves to suppress Lgr5 CSCs and promote anti-tumor immunity, ultimately limiting CRC progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-021-01866-7DOI Listing
July 2021

Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations.

Cancer Cell 2021 Jun 29;39(6):866-882.e11. Epub 2021 Apr 29.

Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.

Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241235PMC
June 2021

Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts.

J Clin Invest 2021 06;131(11)

Department of Medicine, Columbia University, New York, New York, USA.

Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI146987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159701PMC
June 2021

Therapeutic targeting of STAT3 with small interference RNAs and antisense oligonucleotides embedded exosomes in liver fibrosis.

FASEB J 2021 05;35(5):e21557

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hepatic fibrosis is a wound healing response that results in excessive extracellular matrix (ECM) accumulation in response to chronic hepatic injury. Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor associated with the pathogenesis of liver fibrosis. Though a promising potential therapeutic target, there are no specific drug candidates for STAT3. Exosomes are extracellular vesicles generated by all cell types with a capacity to efficiently enter cells across different biological barriers. Here, we utilize exosomes as delivery conduit to specifically target STAT3 in liver fibrosis. Exosomes derived from clinical grade fibroblast-like mesenchymal stem cells (MSCs) were engineered to carry siRNA or antisense oligonucleotide (ASO) targeting STAT3 (iExo or iExo ). Compared to scrambled siRNA control, siRNA-STAT3, or ASO-STAT3, iExo or iExo showed enhanced STAT3 targeting efficiency. iExo or iExo treatments suppressed STAT3 levels and ECM deposition in established liver fibrosis in mice, and significantly improved liver function. iExo restored liver function more efficiently when compared to iExo . Our results identify a novel anti-fibrotic approach for direct targeting of STAT3 with exosomes with immediate translational potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.202002777RRDOI Listing
May 2021

Stabilized epithelial phenotype of cancer cells in primary tumors leads to increased colonization of liver metastasis in pancreatic cancer.

Cell Rep 2021 04;35(2):108990

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is therapeutically recalcitrant and metastatic. Partial epithelial to mesenchymal transition (EMT) is associated with metastasis; however, a causal connection needs further unraveling. Here, we use single-cell RNA sequencing and genetic mouse models to identify the functional roles of partial EMT and epithelial stabilization in PDAC growth and metastasis. A global EMT expression signature identifies ∼50 cancer cell clusters spanning the epithelial-mesenchymal continuum in both human and murine PDACs. The combined genetic suppression of Snail and Twist results in PDAC epithelial stabilization and increased liver metastasis. Genetic deletion of Zeb1 in PDAC cells also leads to liver metastasis associated with cancer cell epithelial stabilization. We demonstrate that epithelial stabilization leads to the enhanced collective migration of cancer cells and modulation of the immune microenvironment, which likely contribute to efficient liver colonization. Our study provides insights into the diverse mechanisms of metastasis in pancreatic cancer and potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.108990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078733PMC
April 2021

Effective delivery of STING agonist using exosomes suppresses tumor growth and enhances antitumor immunity.

J Biol Chem 2021 Jan-Jun;296:100523. Epub 2021 Mar 9.

Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Bioengineering, Rice University, Houston, Texas, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. Electronic address:

The Stimulator of Interferon Genes (STING) pathway is implicated in the innate immune response and is important in both oncogenesis and cancer treatment. Specifically, activation of the cytosolic DNA sensor STING in antigen-presenting cells (APCs) induces a type I interferon response and cytokine production that facilitates antitumor immune therapy. However, use of STING agonists (STINGa) as a cancer therapeutic has been limited by unfavorable pharmacological properties and targeting inefficiency due to rapid clearance and limited uptake into the cytosol. Exosomes, a class of extracellular vesicles shed by all cells are under consideration for their use as effective carriers of drugs owing to their innate ability to be taken up by cells and their biocompatibility for optimal drug biodistribution. Therefore, we engineered exosomes to deliver the STING agonist cyclic GMP-AMP (iExo), to exploit their favorable pharmacokinetics and pharmacodynamics. Selective targeting of the STING pathway in APCs with iExo was associated with superior potency compared with STINGa alone in suppressing B16F10 tumor growth. Moreover, iExo showed superior uptake of STINGa into dendritic cells compared with STINGa alone, which led to increased accumulation of activated CD8 T-cells and an antitumor immune response. Our study highlights the potential of exosomes in general, and iExo specifically, in enhancing cancer therapy outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042450PMC
August 2021

Type I collagen deletion in αSMA myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer.

Cancer Cell 2021 04 4;39(4):548-565.e6. Epub 2021 Mar 4.

Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address:

Stromal desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC) involves significant accumulation of type I collagen (Col1). However, the precise molecular and mechanistic contribution of Col1 in PDAC progression remains unknown. Activated pancreatic stellate cells/αSMA myofibroblasts are major contributors of Col1 in the PDAC stroma. We use a dual-recombinase genetic mouse model of spontaneous PDAC to delete Col1 specifically in myofibroblasts. This results in significant reduction of total stromal Col1 content and accelerates the emergence of PanINs and PDAC, decreasing overall survival. Col1 deletion leads to Cxcl5 upregulation in cancer cells via SOX9. Increase in Cxcl5 is associated with recruitment of myeloid-derived suppressor cells and suppression of CD8 T cells, which can be attenuated with combined targeting of CXCR2 and CCR2 to restrain accelerated PDAC progression in the setting of stromal Col1 deletion. Our results unravel the fundamental role of myofibroblast-derived Co1l in regulating tumor immunity and restraining PDAC progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423173PMC
April 2021

Acute Kidney Injury Instigates Malignant Renal Cell Carcinoma via CXCR2 in Mice with Inactivated and in Proximal Tubular Kidney Epithelial Cells.

Cancer Res 2021 05 8;81(10):2690-2702. Epub 2021 Feb 8.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas.

Renal cell carcinoma (RCC) is one of the most common urologic malignancies with the highest mortality rates worldwide. However, relevant mouse models that recapitulated the genetic alterations found in RCC have been lacking. In this study, we crossed and conditional knockout mice with mice to generate a ; ; ; (GPPY) mouse model, which resulted in the formation of dysplastic lesions involving kidney tubular epithelial cells (TEC), with only approximately 25% of mice developing RCC at an advanced age. Combining CRISPR/Cas9-mediated knockout in these mice increased the frequency of dysplasia, but failed to increase the incidence of RCC. Assessments of whether ischemic injury of TECs in the GPPY kidney without knockout influences the emergence of RCC revealed that advanced RCC predominantly emerged in the contralateral, noninjured kidney with 100% penetrance at a younger age, but rarely in the injured kidney due to severely damaged ischemic TEC. Injured TEC released CXCL1 into the microenvironment that traveled systemically to activate fibroblasts and recruit neutrophils to enable emergence of RCC in the contralateral kidney. Fibroblasts responded to CXCL1 via CXCR2 and recruited tumor-associated neutrophils, which in turn mediated tumor-promoting inflammation and angiogenesis. Treatment with anti-CXCR2 antibodies abolished the emergence of malignant RCC. Collectively, these results demonstrate a defining functional role of systemic inflammation and microenvironment in the emergence of malignant cancer from preestablished dysplastic precursor lesions. SIGNIFICANCE: These results identify a role for CXCL1/CXCR2 and the tumor microenvironment in the development of RCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2690/F1.large.jpg..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-2930DOI Listing
May 2021

Multifunctional Applications of Engineered Extracellular Vesicles in the Treatment of Cancer.

Endocrinology 2021 03;162(3)

Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Extracellular vesicles (EVs) are key players of intercellular communication in the physiological and pathological setting. In cancer, EVs mediate complex signaling mechanisms between cancer cells and the tumor microenvironment (TME), and can influence tumor progression and the response to existing therapies. Importantly, EVs can be loaded with therapeutic agents and modified to display tumor-targeting molecules. In the field of nanomedicine, EVs have been engineered to serve as therapeutic delivery vehicles for several anticancer agents, including antibodies, chemotherapy, compounds, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated endonuclease 9), and small interfering RNA (siRNA). Notably, the engineered EVs were shown to suppress malignant features of cancer cells, to elicit antitumor immunity, and to decrease tumor angiogenesis. Here, we review the EV-based therapies designed to target cancer cells and to educate components of the TME to drive antitumor responses. These studies illustrate the multifunctional applications of EVs in the development of anticancer therapies and their translational potential for cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/endocr/bqaa250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502448PMC
March 2021

Stromal Cells Exhibit Prevalent Genetic Aberrations in Colorectal Cancer.

Cancer Cell 2020 12;38(6):774-775

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioengineering, Rice University, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Cells within the tumor microenvironment can influence tumor progression; however, genetic alterations in stromal cell populations remain largely unexplored. In this issue, Zhou et al. combine multiomics single-cell sequencing and identify prevalent genetic alterations in colorectal cancer stromal cell populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2020.11.003DOI Listing
December 2020

STOX1 deficiency is associated with renin-mediated gestational hypertension and placental defects.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The pathogenesis of preeclampsia and other hypertensive disorders of pregnancy remains poorly defined despite the substantial burden of maternal and neonatal morbidity associated with these conditions. In particular, the role of genetic variants as determinants of disease susceptibility is understudied. Storkhead-box protein 1 (STOX1) was first identified as a preeclampsia risk gene through family-based genetic linkage studies in which loss-of-function variants were proposed to underlie increased preeclampsia susceptibility. We generated a genetic Stox1 loss-of-function mouse model (Stox1 KO) to evaluate whether STOX1 regulates blood pressure in pregnancy. Pregnant Stox1-KO mice developed gestational hypertension evidenced by a significant increase in blood pressure compared with WT by E17.5. While severe renal, placental, or fetal growth abnormalities were not observed, the Stox1-KO phenotype was associated with placental vascular and extracellular matrix abnormalities. Mechanistically, we found that gestational hypertension in Stox1-KO mice resulted from activation of the uteroplacental renin-angiotensin system. This mechanism was supported by showing that treatment of pregnant Stox1-KO mice with an angiotensin II receptor blocker rescued the phenotype. Our study demonstrates the utility of genetic mouse models for uncovering links between genetic variants and effector pathways implicated in the pathogenesis of hypertensive disorders of pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.141588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934881PMC
January 2021

Protection against SARS-CoV-2 by BCG vaccination is not supported by epidemiological analyses.

Sci Rep 2020 10 27;10(1):18377. Epub 2020 Oct 27.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The Bacillus Calmette-Guerin (BCG) vaccine provides protection against tuberculosis (TB), and is thought to provide protection against non-TB infectious diseases. BCG vaccination has recently been proposed as a strategy to prevent infection with SARS-CoV-2 (CoV-2) to combat the COVID-19 outbreak, supported by its potential to boost innate immunity and initial epidemiological analyses which observed reduced severity of COVID-19 in countries with universal BCG vaccination policies. Seventeen clinical trials are currently registered to inform on the benefits of BCG vaccinations upon exposure to CoV-2. Numerous epidemiological analyses showed a correlation between incidence of COVID-19 and BCG vaccination policies. These studies were not systematically corrected for confounding variables. We observed that after correction for confounding variables, most notably testing rates, there was no association between BCG vaccination policy and COVD-19 spread rate or percent mortality. Moreover, we found variables describing co-morbidities, including cardiovascular death rate and smoking prevalence, were significantly associated COVID-19 spread rate and percent mortality, respectively. While reporting biases may confound our observations, our epidemiological findings do not provide evidence to correlate overall BCG vaccination policy with the spread of CoV-2 and its associated mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-75491-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591473PMC
October 2020

Deconstructing tumor heterogeneity: the stromal perspective.

Oncotarget 2020 Oct 6;11(40):3621-3632. Epub 2020 Oct 6.

Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, USA.

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546755PMC
October 2020

Emerging role of bacterial extracellular vesicles in cancer.

Oncogene 2020 11 15;39(46):6951-6960. Epub 2020 Oct 15.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Shedding of microbial extracellular vesicles constitutes a universal mechanism for inter-kingdom and intra-kingdom communication that is conserved among prokaryotic and eukaryotic microbes. In this review we delineate fundamental aspects of bacterial extracellular vesicles (BEVs) including their biogenesis, cargo composition, and interactions with host cells. We critically examine the evidence that BEVs from the host gut microbiome can enter the circulatory system to disseminate to distant organs and tissues. The potential involvement of BEVs in carcinogenesis is evaluated and future research ideas explored. We further discuss the potential of BEVs in microbiome-based liquid biopsies for cancer diagnostics and bioengineering strategies for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-020-01509-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557313PMC
November 2020

Exosomes as mediators of immune regulation and immunotherapy in cancer.

FEBS J 2021 01 3;288(1):10-35. Epub 2020 Oct 3.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Exosomes are nanosized extracellular vesicles of endosomal origin that enclose a multitude of functional biomolecules. Exosomes have emerged as key players of intercellular communication in physiological and pathological conditions. In cancer, depending on the context, exosomes can oppose or potentiate the development of an aggressive tumor microenvironment, thereby impacting tumor progression and clinical outcome. Increasing evidence has established exosomes as important mediators of immune regulation in cancer, as they deliver a plethora of signals that can either support or restrain immunosuppression of lymphoid and myeloid cell populations in tumors. Here, we review the current knowledge related to exosome-mediated regulation of lymphoid (T lymphocytes, B lymphocytes, and NK cells) and myeloid (macrophages, dendritic cells, monocytes, myeloid-derived suppressor cells, and neutrophils) cell populations in cancer. We also discuss the translational potential of engineered exosomes as immunomodulatory agents for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.15558DOI Listing
January 2021

A map of human breast cancer: new players in stromal-immune crosstalk.

EMBO J 2020 10 10;39(19):e106368. Epub 2020 Sep 10.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Prominent accumulation of mesenchymal cells within tumors has long been appreciated, and recent studies suggest molecular and functional diversity of stromal components. In this issue, Wu et al (2020) employed single-cell RNA sequencing of primary human breast tumors and identified new subsets of stromal mesenchymal cells with distinct transcriptional profiles, tissue localization, and associative immune microenvironments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embj.2020106368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527925PMC
October 2020

Heterogeneous antibodies against SARS-CoV-2 spike receptor binding domain and nucleocapsid with implications for COVID-19 immunity.

JCI Insight 2020 09 17;5(18). Epub 2020 Sep 17.

Metastasis Research Center, Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Evaluation of potential immunity against the novel severe acute respiratory syndrome (SARS) coronavirus that emerged in 2019 (SARS-CoV-2) is essential for health, as well as social and economic recovery. Generation of antibody response to SARS-CoV-2 (seroconversion) may inform on acquired immunity from prior exposure, and antibodies against the SARS-CoV-2 spike protein receptor binding domain (S-RBD) are speculated to neutralize virus infection. Some serology assays rely solely on SARS-CoV-2 nucleocapsid protein (N-protein) as the antibody detection antigen; however, whether such immune responses correlate with S-RBD response and COVID-19 immunity remains unknown. Here, we generated a quantitative serological ELISA using recombinant S-RBD and N-protein for the detection of circulating antibodies in 138 serial serum samples from 30 reverse transcription PCR-confirmed, SARS-CoV-2-hospitalized patients, as well as 464 healthy and non-COVID-19 serum samples that were collected between June 2017 and June 2020. Quantitative detection of IgG antibodies against the 2 different viral proteins showed a moderate correlation. Antibodies against N-protein were detected at a rate of 3.6% in healthy and non-COVID-19 sera collected during the pandemic in 2020, whereas 1.9% of these sera were positive for S-RBD. Approximately 86% of individuals positive for S-RBD-binding antibodies exhibited neutralizing capacity, but only 74% of N-protein-positive individuals exhibited neutralizing capacity. Collectively, our studies show that detection of N-protein-binding antibodies does not always correlate with presence of S-RBD-neutralizing antibodies and caution against the extensive use of N-protein-based serology testing for determination of potential COVID-19 immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.142386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526535PMC
September 2020

Enacting national social distancing policies corresponds with dramatic reduction in COVID19 infection rates.

PLoS One 2020 30;15(7):e0236619. Epub 2020 Jul 30.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.

The outbreak the SARS-CoV-2 (CoV-2) virus has resulted in over 6.5 million cases of COVID19, greatly stressing global healthcare infrastructure. Lacking medical prophylactic measures to combat disease spread, many nations have adopted social distancing policies in order to mitigate transmission of CoV-2. While mathematical models have suggested the efficacy of social distancing to curb the spread of CoV-2, there is a lack of systematic studies to quantify the real-world efficacy of these approaches. Here, we first demonstrate that implementation of social distancing policies in US states corresponded with a reduction in COVID19 spread rates, and that the reduction in spread rate is proportional to the average change in mobility. We validate this observation on a worldwide scale by analyzing COVID19 spread rate in 134 nations with varying social distancing policies. Globally, we find that social distancing policies significantly reduced the COVID19 spread rate, with resulting in an estimated 65% reduction (95% CI = 39-80%) in new COVID19 cases over a two week time period. These data suggest that social distancing policies may be a powerful tool to prevent spread of COVID19 in real-world scenarios.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392246PMC
August 2020

Biology and therapeutic potential of mesenchymal stem cell-derived exosomes.

Cancer Sci 2020 Sep 28;111(9):3100-3110. Epub 2020 Jul 28.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Mesenchymal stem cells (MSC) are multipotent stromal cells with the potential to differentiate into several cell types. MSC-based therapy has emerged as a promising strategy for various diseases. Accumulating evidence suggests that the paracrine effects of MSC are partially exerted by the secretion of soluble factors, in particular exosomes. MSC-derived exosomes are involved in intercellular communication through transfer of proteins, RNA, DNA and bioactive lipids, which might constitute a novel intercellular communication mode. This review illustrates the current knowledge on the composition and biological functions as well as the therapeutic potential of MSC-derived exosomes in cancer, with a focus on clinical translation opportunities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469857PMC
September 2020

Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis.

Sci Signal 2020 06 9;13(635). Epub 2020 Jun 9.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of (which encodes Twist) or (which encodes Snail) in VE-cadherin or Tie1 endothelial cells inhibited the emergence of EndMT and improved kidney fibrosis in two different kidney injury/fibrosis mouse models. Suppression of EndMT limited peritubular vascular leakage, reduced tissue hypoxia, and preserved tubular epithelial health and function. Hypoxia, which was exacerbated by EndMT, resulted in increased Myc abundance in tubular epithelial cells, enhanced glycolysis, and suppression of fatty acid oxidation. Pharmacological suppression or epithelial-specific genetic ablation of Myc in tubular epithelial cells ameliorated fibrosis and restored renal parenchymal function and metabolic homeostasis. Together, these findings demonstrate a functional role for EndMT in the response to kidney capillary endothelial injury and highlight the contribution of endothelial-epithelial cross-talk in the development of kidney fibrosis with a potential for therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scisignal.aaz2597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790440PMC
June 2020

Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer.

Cell Rep 2020 06;31(9):107701

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.107701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339325PMC
June 2020

Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer.

Cancer Discov 2020 07 27;10(7):1058-1077. Epub 2020 Apr 27.

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible ; PDAC mouse model, gain-of-function screens of epigenetic regulators identified as the top hit enabling KRAS* independent tumor growth. -driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses , a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2 macrophages. Correspondingly, enforced promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME. SIGNIFICANCE: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-19-0597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334087PMC
July 2020

Exosomes as a Multicomponent Biomarker Platform in Cancer.

Trends Cancer 2020 09 16;6(9):767-774. Epub 2020 Apr 16.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer is a complex disease that is associated with genetic aberrations and subsequent cellular and noncellular host responses. Tumors harbor diverse cell types that engage in a dynamic interplay to sustain cancer-specific signaling networks. A component of such cellular communication is the production and exchange of various types of extracellular vesicle (EV). Exosomes are small EVs with growing recognition for their role in cancer progression and resistance to therapy. The unique biogenesis of exosomes, their ubiquitous production by all cell types, and their biological features in liquid biopsies have generated excitement for their potential as cancer biomarkers. Here, we discuss the challenges and utility of exosomes as multiparameter biomarker platforms for the detection of cancer. Exosomes reflect heterogeneous biological changes associated with growing tumors, potentially offering a more comprehensive assessment of cancer diagnosis, prognosis, and progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trecan.2020.03.007DOI Listing
September 2020
-->