Mitchell Gross | University of Southern California (original) (raw)

Papers by Mitchell Gross

ABSTRACT This paper reports three-dimensional (3D) localized cytolysis of cell spheroids by Self ... more ABSTRACT This paper reports three-dimensional (3D) localized cytolysis of cell spheroids by Self Focusing Acoustic Transducers (SFAT) with 10 mm focal length. In previous studies, it has been demonstrated that an SFAT with 800 μm focal length caused localized cytolysis on monolayer cells. Since practical ultrasonic cancer therapeutics are usually performed in a 3D biological environment, an SFAT having a long penetration depth and focusing acoustic energy at 10 mm within an area of 160 μm in diameter has been designed and fabricated. Also, the acoustic intensity thresholds (AITs) of spheroids for cancer-specific cytolysis of malignant cells (breast cancer MCF-7 and prostate cancer 22RV1) are investigated. According to experiments with the spheroids in 3D Matrigel environment, the crosslinks between Matrigel and spheroids greatly increase AITs of 22RV1 and MCF-7 cell spheroids from 0.11 W/cm2 to 11.10 ~ 15.14 W/cm2. In addition, in both “unsolidified” (without crosslink) and solidified (with crosslink) Matrigel environments, spheroids of non-malignant cell line MCF-10A are not lysed even with two to three times higher acoustic intensities than the AITs of MCF-7. Therefore, the general trend associating a lower AIT with a more malignant still stands for MCF-7 and MCF-10A 3D spheroids in 3D Matrigel environment.

Prostate Cancer and Prostatic Diseases, Jun 28, 2016

Androgen deprivation therapy (ADT), a primary treatment for locally advanced or metastatic prosta... more Androgen deprivation therapy (ADT), a primary treatment for locally advanced or metastatic prostate cancer, is associated with the adverse effects on numerous physiologic parameters, including alterations in cardiometabolic variables that overlap with components of the metabolic syndrome (MetS). As MetS is an established risk factor for cardiovascular mortality and treatment for prostate cancer has been associated with the development of MetS, interventions targeting cardiometabolic factors have been investigated in prostate cancer patients to attenuate the detrimental effects of ADT. Much support exists for exercise interventions in improving MetS variables in insulin-resistant adults, but less evidence is available in men with prostate cancer. Regular exercise, when performed at appropriate intensities and volumes, can elicit improvements in ADT-related adverse effects, including MetS, and contributes to the growing body of literature supporting the role of exercise in cancer survivorship. This review (1) discusses the biologic inter-relationship between prostate cancer, ADT and MetS, (2) evaluates the current literature in support of exercise in targeting MetS and (3) describes the physiological mechanisms by which exercise may favorably alter MetS risk factors in prostate cancer patients on ADT.

PLOS ONE, Aug 1, 2014

Timely characterization of a cancer's evolution is required to predict treatment efficacy and to ... more Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC subpopulations that differed in both AR genotype and expression phenotype. While AR-cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients.

Interactions between epithelial and stromal cells are important in the development of prostate ca... more Interactions between epithelial and stromal cells are important in the development of prostate cancer (PCa). Cancer-associated fibroblasts (CAFs) have been to support tumor progression, metastasis, and differentiation. Androgen receptor (AR) and related pathways are known to support the growth and survival of prostate epithelial cancer cells, the roles of AR-dependent processes in cancerous stroma are less clear. We sought to investigate if AR-dependent pathways present in CAF cells influence the growth and tumorogencity of epithelial cancer cells in relation to androgen-deprivation therapy in prostate cancer. Murine CAFs were isolated from a well-described PTEN-dependent cancer mouse model. A co-culture system was developed based on multiple lines of murine CAFs grown along with human prostate cancer epithelial cells, and a murine-specific anti-sense oligonucleotide (ASO) against murine AR was used to specifically suppress AR expression in murine CAFs in this system. Using this co-culture system, we found that murine CAFs promoted cell proliferation and colony formation in several human prostate cancer cell lines. Further, these processes were decreased by suppression of AR-expression in CAFs. Expression of genes related to tumorogenicity in epithelial cells were investigated by real-time quantitative PCR. Markers associated with epithelial-mesenchymal transition (EMT) and stemness were increased in human prostate cancer cells grown with low-AR CAFs. Our data indicates that suppression of AR in CAFs results in down-regulation in the growth and tumorogenecity of prostate cancer cells through pathways related to EMT and “cell reprograming”. As such, development of therapies which inhibit the tumor-promoting pathways present in stromal cells may be one approach to improve the treatment of prostate cancer. Citation Format: Chun-Peng Liao, Leng-Ying Chen, Andrea Luethy, Youngsoo Kim, Robert MacLeod, Mitchell Gross. Androgen signaling in cancer-associated fibroblasts contributes to progression of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-268.

PLOS ONE, Feb 18, 2015

<p>Subcellular protein fractionation was carried out in LNCaP, C4-2B, PC-3 and DU145 cells,... more <p>Subcellular protein fractionation was carried out in LNCaP, C4-2B, PC-3 and DU145 cells, as well as PHPECs. The amount of protein loaded for each fraction is indicated on the panels. Western blotting was performed using anti-ICD GPR158 antibody. Specific protein markers were used to validate and confirm the purity of the five subcellular fractions examined: cytoplasmic extract (CE) = alpha-tubulin, membrane extract (ME) = EGFR, soluble nuclear extract (NE) = Sp1, chromatin-bound nuclear extract (CBE) = histone H3 and insoluble cytoskeletal extract (CSE) lamin A/C. The percentage of GPR158 protein present in each fraction was calculated with respect to the total amount of protein in all fractions using Image J analysis of protein band intensities. The data are representative of two independent experiments.</p

IEEE Access, 2021

Focused ultrasound (FUS) has proven its efficacy in non-invasive, radiation-free cancer treatment... more Focused ultrasound (FUS) has proven its efficacy in non-invasive, radiation-free cancer treatment. However, the commonly used low-frequency high-intensity focused ultrasound (HIFU) destroys both cancerous and healthy tissues non-specifically through extreme heat and inertial cavitation with low spatial resolution. To address this issue, we evaluate the therapeutic effects of pulsed (60 Hz pulse repetition frequency, 1.45 ms pulse width) high-frequency (20.7 MHz) medium-intensity (spatial-peak pulse-average intensity I SPPA < 279.1 W/cm 2 , spatial-peak temporal-average intensity I SPTA < 24.3 W/cm 2 ) focused ultrasound (pHFMIFU) for selective cancer treatment without thermal damage and with low risk of inertial cavitation (mechanical index < 0.66), in an in vivo subcutaneous B16F10 melanoma tumor growth model in mice. The pHFMIFU with 104 µm focal diameter is generated by a microfabricated self-focusing acoustic transducer (SFAT) with a Fresnel acoustic lens. A three-axis positioning system has been developed for automatic scanning of the transducer to cover a larger treatment volume, while a water-cooling system is custom-built for dissipating non-acoustic heat from the transducer surface. Initial testing revealed that pHFMIFU treatment can be applied to a living animal while maintaining skin temperature under 35.6 • C without damaging normal skin and tissue. After eleven days of treatment with pHFMIFU, the treated tumors were significantly smaller with large areas of necrosis and apoptosis in the treatment field compared to untreated controls. Potential mechanisms of this selective, non-thermal killing effect, as well as possible causes of and solutions to the variation in treatment results, have been analyzed and proposed. The pHFMIFU could potentially be used as a new therapeutic modality for safer cancer treatment especially in critical body regions, due to its cancer-specific effects and high spatial resolution. INDEX TERMS High-frequency focused ultrasound, in vivo experiment, non-invasive therapy, selective cancer treatment, self-focusing acoustic transducers (SFAT), ultrasound therapy.

Revista española de medicina nuclear e imagen molecular, Jul 1, 2012

Journal of Clinical Oncology, Jan 10, 2016

297 Background: Interactions between epithelial and stroma cells are important in the development... more 297 Background: Interactions between epithelial and stroma cells are important in the development of prostate cancer (PCa). Cancer-associated fibroblasts (CAFs) have been to support tumor progression, metastasis, and differentiation. Androgen receptor (AR) and related pathways are known to support the growth and survival of prostate epithelial cancer cells, the roles of AR-dependent processes in cancerous stroma are less clear. We sought to investigate if AR-dependent pathways present in CAF cells influence the growth and tumorogencity of epithelial cancer cells in relation to androgen-deprivation therapy in prostate cancer. Methods: Murine CAFs were isolated from a well-described PTEN-dependent cancer mouse model (Liao, et al Cancer Res, 2010. 70(18):7294). A co-culture system was developed based on multiple lines of murine CAFs grown along with human prostate cancer epithelial cells, and a murine-specific anti-sense oligonucleotide (ASO) against murine AR was used to specifically suppress AR expression in murine CAFs in this system. RT-PCR was used to investigate changes in gene expression. Results: Using this co-culture system, we found that murine CAFs promoted cell proliferation and colony formation in several human prostate cancer cell lines. Further, these processes were decreased by suppression of AR-expression in CAFs. Expression of genes related to tumorigenicity in epithelial cells were investigated. Markers associated with epithelial-mesenchymal transition (EMT, N-Cad) and “stemness” (OCT4, Sox2, Nanog) were increased in human prostate cancer cells grown with low-AR CAFs. Conclusions: Our data indicates that suppression of AR in CAFs results in down-regulation in the growth and tumorigenicity of prostate cancer cells through pathways related to EMT and “cell reprograming”. As such, development of therapies which inhibit the tumor-promoting pathways present in stromal cells may be one approach to improve the treatment of prostate cancer.

BMC Cancer, Apr 3, 2018

Background: Prostate cancer patients on androgen deprivation therapy (ADT) experience adverse eff... more Background: Prostate cancer patients on androgen deprivation therapy (ADT) experience adverse effects such as lean mass loss, known as sarcopenia, fat gain, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance training can increase lean mass, reduce body fat, and improve physical function and quality of life, but no exercise interventions in prostate cancer patients on ADT have concomitantly improved body composition and MetS. This pilot trial investigated 12 weeks of resistance training on body composition and MetS changes in prostate cancer patients on ADT. An exploratory aim examined if a combined approach of training and protein supplementation would elicit greater changes in body composition. Methods: Prostate cancer patients on ADT were randomized to resistance training and protein supplementation (TRAINPRO), resistance training (TRAIN), protein supplementation (PRO), or control stretching (STRETCH). Exercise groups (EXE = TRAINPRO, TRAIN) performed supervised exercise 3 days per week for 12 weeks, while non-exercise groups (NoEXE = PRO, STRETCH) performed a home-based stretching program. TRAINPRO and PRO received 50 g⋅day - 1 of whey protein. The primary outcome was change in lean mass assessed through dual energy x-ray absorptiometry. Secondary outcomes examined changes in sarcopenia, assessed through appendicular skeletal mass (ASM) index (kg/ m 2 ), body fat %, strength, physical function, quality of life, MetS score and the MetS components of waist circumference, blood pressure, glucose, high-density lipoprotein-cholesterol, and triglyceride levels. Results: A total of 37 participants were randomized; 32 participated in the intervention (EXE n = 13; NoEXE n = 19). At baseline, 43.8% of participants were sarcopenic and 40.6% met the criteria for MetS. Post-intervention, EXE significantly improved lean mass (d = 0.9), sarcopenia prevalence (d = 0.8), body fat % (d = 1.1), strength (d = 0.8-3.0), and prostate cancer-specific quality of life (d = 0.9) compared to NoEXE (p < 0.05). No significant differences were observed between groups for physical function or MetS-related variables except waist circumference (d = 0.8). Conclusions: A 12-week resistance training intervention effectively improved sarcopenia, body fat %, strength and quality of life in hypogonadal prostate cancer patients, but did not change MetS or physical function. PRO did not offer additional benefit in improving body composition.

PDF file, 299KB, Protein level changes associated with gefitinib treatment in NSCLC tissue.

PDF file, 47KB, Protein Identification for Solid Phase Extraction of Glycoproteins (SPEG)with 16 ... more PDF file, 47KB, Protein Identification for Solid Phase Extraction of Glycoproteins (SPEG)with 16 hours of gefitinib treatment.

PDF file, 5465KB, Quantitation tables for proteins identified and quantified.

$Research paper thumbnail of Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients Presented in part at the American Society of Clinical Oncology Multidisciplinary Prostate Cancer Symposium, February 17–19, 2005, Orlando, Florida; and the American Society of Clinical Oncolog...$

Wiley Subscription Services, Inc., A Wiley Company, Aug 1, 2007

Journal of Controlled Release, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Oncogene, 2018

Anterior gradient 2 (AGR2) is a member of the protein disulfide isomerase (PDI) family, which pla... more Anterior gradient 2 (AGR2) is a member of the protein disulfide isomerase (PDI) family, which plays a role in the regulation of protein homeostasis and the unfolded protein response pathway (UPR). AGR2 has also been characterized as a protooncogene and a potential cancer biomarker. Cellular localization of AGR2 is emerging as a key component for understanding the role of AGR2 as a proto-oncogene. Here, we provide evidence that extracellular AGR2 (eAGR2) promotes tumor metastasis in various in vivo models. To further characterize the role of the intracellular-resident versus extracellular protein, we performed a comprehensive protein-protein interaction screen. Based on these results, we identify AGR2 as an interacting partner of the mTORC2 pathway. Importantly, our data indicates that eAGR2 promotes increased phosphorylation of RICTOR (T1135), while intracellular AGR2 (iAGR2) antagonizes its levels and phosphorylation. Localization of AGR2 also has opposing effects on the Hippo pathway, spheroid formation, and response to chemotherapy in vitro. Collectively, our results identify disparate phenotypes predicated on AGR2 localization. Our findings also provide credence for screening of eAGR2 to guide therapeutic decisions.

Annals of Oncology, 2018

The phase 2 TRITON2 (NCT02952534) and phase 3 TRITON3 (NCT02975934) studies are evaluating the po... more The phase 2 TRITON2 (NCT02952534) and phase 3 TRITON3 (NCT02975934) studies are evaluating the poly(ADP-ribose) polymerase inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or other homologous recombination repair (HRR) gene. Here we present initial results from central genomic screening of plasma ctDNA and tissue samples in TRITON2 and TRITON3.