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Publications (242)
Deep proteomic profiling of rare cell populations has been constrained by sample input requirements. Here, we present DROPPS (droplet-based one-pot preparation for proteomic samples), an accessible low-input platform that generates high-fidelity proteomic profiles of 100–2,500 cells. By applying DROPPS within the mammary epithelium, we elucidated t...
A lipid metabolism gene signature is associated with the risk of estrogen negative breast cancer (ER-BC). In vitro, lipid exposure alters histone methylation affecting gene expression and increasing flux through various metabolic reactions; but little is known about the mechanism(s) linking lipids and epigenetic reprogramming with the genesis of ER...
Pancreatic ductal adenocarcinoma (PDAC) has a complex disease pathobiology and poor treatment options, emphasizing the need for novel therapeutic targets. Hub genes have high connectivity (i.e., exceptionally many interaction partners), for example, certain proteases with numerous interaction partners. Thereby, hub genes are often central biologica...
The development of novel leukemic stem cell (LSC)-targeted therapeutics, which spare hematopoietic stem cells (HSC), is an urgent goal towards reducing the high, LSC-driven, relapse rates in acute myeloid leukemia (AML) patients. Towards elucidating key post-transcriptional networks underlying LSC maintenance we previously performed an in vivo pool...
It has been nearly 3 decades since the discovery of the BRCA1/2 genes and their link to breast cancer risk, with prophylactic mastectomy remaining the primary management option for these high-risk mutation carriers. The current paucity of interception strategies is due to undefined, targetable cancer precursor populations in the high-risk breast. D...
Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenv...
Integration and mining of bioimaging data remains a challenge and lags behind the rapidly expanding digital pathology field. We introduce Hourglass, an open‐access analytical framework that streamlines biology‐driven visualization, interrogation, and statistical assessment of multiparametric datasets. Cognizant of tissue and clinical heterogeneity,...
Deep proteomic profiling of rare cell populations has been constrained by sample input requirements. Here, we present DROPPS, an accessible low-input platform that generates high-fidelity proteomic profiles of 100 - 2,500 cells. By applying DROPPS within the mammary epithelium, we elucidated the connection between mitochondrial activity and clonoge...
Background:
Systemic inflammatory scores may aid prognostication and patient selection for trials. We compared five scores in advanced pancreatic adenocarcinoma (PDAC).
Methods:
Unresectable/metastatic PDAC patients enrolled in the Comprehensive Molecular Characterisation of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selectio...
Effective treatments for Pancreatic ductal adenocarcinoma (PDAC) remain an urgent need. Integration of molecular PDAC subtypes into clinical trials could enable translational insights into how we might refine existing and emerging therapies to improve treatment options, yet this requires robust clinically suitable marker genes and a better understa...
Recent advances in digital pathology have led to an explosion in high-content multidimensional imaging approaches. Yet, our ability to gainfully process, visualize, integrate and mine the resulting mass of bioimaging data remains a challenge. We have developed Hourglass, an open access user-friendly software that streamlines complex biology-driven...
Objectives
Transcriptional classifiers (Bailey, Moffitt and Collison) are key prognostic factors of pancreatic ductal adenocarcinoma (PDAC). Among these classifiers, the squamous, basal-like, and quasimesenchymal subtypes overlap and have inferior survival. Currently, only an invasive biopsy can determine these subtypes, possibly resulting in treat...
Driven by the lack of targeted therapies, triple-negative breast cancers (TNBCs) have the worst overall survival of all breast cancer subtypes. Considering that cell surface proteins are favorable drug targets and are predominantly glycosylated, glycoproteome profiling has significant potential to facilitate the identification of much-needed drug t...
Driven by the lack of targeted therapies, triple negative breast cancers (TNBC) have the worst overall survival of all breast cancer subtypes. Considering cell surface proteins are favorable drug targets and are predominantly glycosylated, glycoproteome profiling has significant potential to facilitate the identification of much-needed drug targets...
Breast cancer risk for carriers of BRCA1 pathological variants is modified by genetic factors. Genetic variation in HMMR may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood. Here, we depict an interplay of molecular, cellular, and...
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Del...
Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. We recently deconvoluted regional heterogeneity in the human PDAC stroma to assess its role in disease progression and discovered two types of ‘sub-tumor microenvironments’ (subTMEs), called ‘reactive’ and ‘deserted...
Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically...
Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was...
Bone marrow (BM) is the primary site of hematopoiesis and is responsible for a lifelong supply of all blood cell lineages. The process of hematopoiesis follows key intrinsic programs that also integrate instructive signals from the BM niche. First identified as an erythropoietin potentiating factor, tissue inhibitor of metalloproteinase (TIMP) prot...
The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA doublestrand
breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs
promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prog...
It has long been assumed that all normal cells have the same capacity to engage homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DNA double-strand breaks (DSBs), a concept exploited for DNA-damaging chemotherapeutics. We show that mammary epithelial lineage dictates the DSB repair pathway choice. Primary mammary proteom...
Cancer metabolism adapts the metabolic network of its tissue of origin. However, breast cancer is not a disease of a single origin. Multiple epithelial populations serve as the culprit cell of origin for specific breast cancer subtypes, yet our knowledge of the metabolic network of normal mammary epithelial cells is limited. Using a multi-omic appr...
Pancreatic ductal adenocarcinoma (PDAC) remains resistant to most treatments and demonstrates a complex pathobiology. Here, we deconvolute regional heterogeneity in the human PDAC tumor microenvironment (TME), a long-standing obstacle, to define precise stromal contributions to PDAC progression. Large scale integration of histology-guided multiOMIC...
Pancreatic ductal adenocarcinoma (PDAC) remains mostly untreatable while its incidence is on the rise. PDAC stroma should be a reservoir for novel therapeutic targets. Yet, stromal cellular complexity and an extensive intratumoral heterogeneity in human patients have left the functions of PDAC stroma poorly understood and likely hamper its targetin...
Ewing sarcoma (ES) is a poorly differentiated bone and soft tissue tumor of high metastatic potential. ES mainly affects children, adolescents, and young adults (AYAs) at a frequency of ~1.5 cases per million globally. Ewing neoplasms strikingly converge on a single recurrent initiating event, which is a chromosomal translocation that generates a f...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet knowledge surrounding the metabolic network of normal mammary epithelial cells is limited. Here, we show th...
Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble factors in the niche respond to stress and enable progenitor activity. Metalloproteases (MMPs, ADAMs, ADAMTSs) and their inhibitors (TIMPs) control certain physical and biochemical...
Regulated growth plate activity is essential for postnatal bone development and body stature, yet the systems regulating epiphyseal fusion are poorly understood. Here, we show that the tissue inhibitors of metalloprotease (TIMP) gene family is essential for normal bone growth after birth. Whole-body quadruple-knockout mice lacking all four TIMPs ha...
Breast cancer prevention is daunting, yet not an unsurmountable goal. Mammary stem and progenitors have been proposed as the cells-of-origin in breast cancer. Here, we present the concept of limiting these breast cancer precursors as a risk reduction approach in high-risk women. A wealth of information now exists for phenotypic and functional chara...
The heterogeneity of breast cancer makes current therapies challenging. Metformin, the anti-diabetic drug, has shown promising anti-cancer activities in epidemiological studies and breast cancer models. Yet, how metformin alters the normal adult breast tissue remains elusive. We demonstrate metformin intake at a clinically relevant dose impacts the...
The mammary gland experiences substantial remodeling and regeneration during development and reproductive life, facilitated by stem cells and progenitors that act in concert with physiological stimuli. While studies have focused on deciphering regenerative cells within the parenchymal epithelium, cell lineages in the stroma that may directly contri...
Leveraging the conserved cancer genomes across mammals has the potential to transform driver gene discovery in orphan cancers. Here, we combine cross-species genomics with validation across human-dog-mouse systems to uncover a new bone tumor suppressor gene. Comparative genomics of spontaneous human and dog osteosarcomas (OS) expose Disks Large Hom...
The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor pro...
Deregulated proteolysis invariably underlies most human diseases including bone pathologies. Metalloproteinases constitute the largest of the five protease families, and the metzincin metalloproteinases are inhibited by the four tissue inhibitors of metalloproteinase called TIMPs. We hypothesized that Timp genes are essential for skeletal homeostas...
Breast cancer is the most common cancer in females. The number of years menstruating and length of an individual menstrual cycle have been implicated in increased breast cancer risk. At present, the proliferative changes within an individual reproductive cycle or variations in the estrous cycle in the normal mammary gland are poorly understood. Her...
The era of cancer genomics now provides an opportunity to discover novel determinants of osteosarcoma (OS), the most common primary bone cancer in children and adolescents known for its poor prognosis due to lung metastasis. Here, we identify CDH4 amplification in 43.6% of human osteosarcoma using array CGH and demonstrate its critical role in oste...
The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult...
The supplement can be found at the following link at Biomedical Advances.
http://biomedical-advances.org/cancer-20181-4/
Extracellular vesicles (EVs) have emerged as pivotal mediators of intercellular communications in local and distant microenvironments under patho/physiological conditions. EVs contain bioactive materials such as proteins, RNA transcripts, microRNAs and even DNAs, and recent work on their protein profiles has revealed the existence of metalloprotein...
Bioassays of planarian neoplasia highlight the potential of these organisms as useful standards to assess whether environmental toxins such as cadmium promote tumorigenesis. These studies complement other investigations into the exceptional healing and regeneration of planarians-processes that are driven by a population of active stem cells, or neo...
A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous e...
Gene expression profiling of WapCreC;Brca1;p53 and WapCreC;Rank;Brca1;p53 tumors.
Genotyped iCOGS variants and breast cancer association in BRCA1 mutation carriers.
Histopathologic assessment.
Histological assessment of tumors from WapCreC;Brca1;p53 and WapCreC;Rank;Brca1;p53 mutant mice.
Detection of proliferation and DNA damage in WapCreC;Brca1;p53 and WapCreC;Rank;Brca1;p53 mammary tumors.
Analysis of a tumor free, 2 year old WapCreC;Rank;Brca1;p53 triple mutant female.
Genotyped iCOGS variants and breast cancer association in BRCA2 mutation carriers.
Cre-mediated deletion efficiency in K5Cre and WapCreC mice using a Rosa26eYFP reporter line.
DNA damage and epithelial origin of WapCreC;Brca1;p53 and WapCreC;Rank;Brca1;p53 tumors.
Generation of WapCreC;Brca1;p53 double and WapCreC;Rank;Brca1;p53 triple knockout mice.
Pharmacological RANKL inhibition prevents the development of pre-neoplastic regions.
RANKL and RANK protein expression in human breast tumors irrespective of BRCA status.
Generation of K5Cre;Brca1;p53 double and K5Cre;Rank;Brca1;p53 triple knockout mice.
Rank deletion in basal mammary epithelial cells reduces Brca1;p53 mutation-driven hyperplastic proliferation.
Analysis of murine mammary progenitor cells.
Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that geneti...
The tumor stroma has the capacity to drive cancer progression, although mechanisms governing these effects are incompletely understood. Recently, we reported the tissue inhibitor of metalloproteinases (Timp) deletion in fibroblasts unleashes the emergence of cancer-associated fibroblast (CAF) functions and identified a novel mode of stromal-tumor c...
Osteosarcoma (OS) is the most common primary bone cancer, which occurs primarily in children and adolescents, severely affecting survivors' quality of life. Despite its chemosensitivity and treatment advances, long-term survival rates for OS patients have stagnated over the last 20 years. Thus, it is necessary to develop new molecularly targeted th...
In Reply Our Editorial provides insight into plausible biological phenomena that may underlie the menopausal hormone therapy influence on breast cancer risk in the Women’s Health Initiative randomized controlled trials reported by Chlebowski et al.1 We addressed the significant increase in breast cancer risk resulting from estrogen + medroxyprogest...
Background:
Altered expression and activity of proteases is implicated in inflammation and cancer progression. An important negative regulator of protease activity is TIMP3 (tissue inhibitor of metalloproteinase 3). TIMP3 expression is lacking in many cancers including advanced prostate cancer, and this may facilitate invasion and metastasis by al...
Systemic and local signals must be integrated by mammary stem and progenitor cells to regulate their cyclic growth and turnover in the adult gland. Here, we show RANK-positive luminal progenitors exhibiting WNT pathway activation are selectively expanded in the human breast during the progesterone-high menstrual phase. To investigate underlying mec...
Breast cancer animal models incorporating medroxyprogesterone acetate, the same compound used in the WHI trials, have shown its potent capacity to promote mammary tumors through key mitogenic signals that stimulate the mammary epithelium.⁶ Accumulating evidence suggests that mammary stem cells and progenitors are the likely “cells-of-origin” for di...
Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes...
Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3-⁄- mice have delayed tumor onset and 36% of MMTV-Neu Timp3-⁄- mice...
Progesterone drives mammary stem and progenitor cell dynamics through paracrine mechanisms that are currently not well understood. Here, we demonstrate that CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), is a crucial instructor of hormone-induced mammary stem and progenitor cell function. Progesterone elicits specific changes in t...
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibit...
Inflammation enables human cancers and is a critical promoter of hepatocellular carcinoma (HCC). TIMP3 (Tissue inhibitor of metalloproteinase 3), a natural metalloproteinase inhibitor, controls cytokine and growth factor bioavailability to keep inflammation in check and regulate cell survival in the liver. TIMP3 is also found silenced in human canc...
Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase ac...
Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further dep...
Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have iso...
Protein kinase A (PKA) hyperactivation causes hereditary endocrine neoplasias; however, its role in sporadic epithelial cancers is unknown. Here, we show that heightened PKA activity in the mammary epithelium generates tumors. Mammary-restricted biallelic ablation of Prkar1a, which encodes for the critical type-I PKA regulatory subunit, induced spo...
In this issue of Developmental Cell, Forster et al. (2014) show that the basal myoepithelial cell layer directs the final maturation of the adjacent luminal cell sheet during pregnancy. Do all mammary epithelial cells both give and take instructions from others to create the milk production machinery?
Interleukin (IL)-12 is the key cytokine in the initiation of a Th1 response and has shown promise as an anti-cancer agent; however, clinical trials involving IL-12 have been unsuccessful due to toxic side-effects. To address this issue, lentiviral vectors were used to transduce tumour cell lines that were injected as an autologous tumour cell vacci...
To test if proteolysis is involved in tumor cell extravasation, we developed an in vitro model where tumor cells cross an endothelial monolayer cultured on a basement membrane. Using this model we classified the ability of the cells to transmigrate through the endothelial cell barrier onto the underlying matrix, and scored this invasion according t...
Lifetime exposure to ovarian hormones plays a crucial role in determining a woman's risk for breast cancer: the risk of developing breast cancer is positively correlated with the number of ovarian-hormone-dependent menstrual cycles. Progesterone is an ovarian steroid hormone that peaks during the luteal phase of the female menstrual cycle. Recent r...
Over the past 50 years, steady growth in the field of metalloproteinase biology has shown that the degradation of extracellular matrix components represents only a fraction of the functions performed by these enzymes and has highlighted their fundamental roles in immunity. Metalloproteinases regulate aspects of immune cell development, effector fun...
