Ori Maller
University of California, San Francisco
CancerInternal medicinePhenotypeEndocrinologyFunction (biology)PathologyCellInterleukin 12Matrix (biology)Stromal cellChemistryExtracellular matrixIntegrinMesenchymal stem cellImmunologyIn vivoMammary tumorInflammationImmunotherapyMammary glandMatrigelCytokineMetastasisImmunityLamininFibroblastFibrosisInvolution (medicine)Mammary EpitheliumProteomicsCancer researchStromaEpitheliumBreast cancerCarcinogenesisMedicineFibronectinBiologyImmune systemCell biology
Publications 18
Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognosis and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone-marrow derived mesenchymal stromal (or Stem) cells (MSCs) that are engineered to express two potent immune-modulatory cytokines, IL-12 and IL-21. Int...
#1Allison P. Drain (UCSF: University of California, San Francisco)H-Index: 5
#2Nastaran Zahir (UPenn: University of Pennsylvania)H-Index: 4
Last. Valerie M. Weaver (UCSF: University of California, San Francisco)H-Index: 87
view all 14 authors...
Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids inte...
#1Ori Maller (UCSF: University of California, San Francisco)H-Index: 9
#2Allison P. Drain (UCSF: University of California, San Francisco)H-Index: 5
Last. Valerie M. WeaverH-Index: 87
view all 26 authors...
Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with ...
8 CitationsSource
While immunotherapies based on single recombinant cytokines such as IL12 and IL21 have shown great promise in preclinical models of solid tumors, clinical translation has proven challenging due to limited mechanisms of action, narrow therapeutic windows upon systemic administration, and short half-lives resulting in poor pharmacokinetics and distribution. Thus, there is a need for tumor-localized cytokine therapies capable of driving sustained efficacy with a wide therapeutic window. SENTI-101 i...
#1J. Matthew Barnes (UCSF: University of California, San Francisco)H-Index: 12
#2Shelly Kaushik (UCSF: University of California, San Francisco)H-Index: 7
Last. Valerie M. WeaverH-Index: 87
view all 22 authors...
Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-f...
37 CitationsSource
#1Alexander S. Barrett (University of Colorado Denver)H-Index: 10
#2Ori Maller (UCSF: University of California, San Francisco)H-Index: 9
Last. Kirk C. Hansen (University of Colorado Denver)H-Index: 67
view all 5 authors...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a severe fibrotic component that compromises treatment, alters the immune cell profile and contributes to patient mortality. It has been shown that early on in this process, dynamic changes in tissue biomechanics play an integral role in supporting pancreatic cancer development and progression. Despite the acknowledgement of its importance, a granular view of how stromal composition changes during the course of PDAC progression...
5 CitationsSource
#1Erica T. Goddard (OHSU: Oregon Health & Science University)H-Index: 6
#2Ryan C. Hill (University of Colorado Denver)H-Index: 23
Last. Pepper Schedin (Anschutz Medical Campus)H-Index: 38
view all 11 authors...
Postpartum breast cancer patients are at increased risk for metastasis compared to age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the post-lactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, ECM remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced l...
25 CitationsSource
#1Erica T. Goddard (OHSU: Oregon Health & Science University)H-Index: 6
#2Ryan C. Hill (Anschutz Medical Campus)H-Index: 23
Last. Pepper Schedin (Anschutz Medical Campus)H-Index: 38
view all 9 authors...
Abstract Normal epithelium exists within a dynamic extracellular matrix (ECM) that is tuned to regulate tissue specific epithelial cell function. As such, ECM contributes to tissue homeostasis, differentiation, and disease, including cancer. Though it is now recognized that the functional unit of normal and transformed epithelium is the epithelial cell and its adjacent ECM, we lack a basic understanding of tissue-specific ECM composition and abundance, as well as how physiologic changes in ECM i...
49 CitationsSource
#1Ori Maller (UCSF: University of California, San Francisco)H-Index: 9
#2Luke Cassereau (UCSF: University of California, San Francisco)H-Index: 8
Last. Valerie M. Weaver (UCSF: University of California, San Francisco)H-Index: 87
view all 11 authors...
We established a positive correlation between a fibrotic phenotype in human breast tumors — especially the Her2 and basal-like breast cancer subtypes — and CD45 and CD68 positive immune cell infiltration. We were interested in elucidating how this fibrotic phenotype may influence the immune response. To address this question, we examined if matrix stiffness alters the function of STAT3, a central regulator of tumor inflammation. We hypothesize that tissue fibrosis promotes STAT3 signaling in mam...
#1Ori MallerH-Index: 9
#2Valerie M. WeaverH-Index: 87
Abstract : Human breast tumors are highly fibrotic and their ECMs are stiffer relative to benign lesions. More recently, we established positive correlations between the number and location of infiltrating immune cells and ECM stiffness in human breast tumors. This has led us to hypothesize that TAMs drive tissue fibrosis and subsequently may stimulate inflammatory signaling. Using the MMTV-PyMT model, early macrophage not only ablated lung metastases, but demonstrated an anti-fibrotic role for ...