Research Highlight


a) Bioluminescent SMAD4 knockout human PDA cell lines with reconstituted SMAD4 have a significantly decreased level of metastasis in the lung upon tail vein injection compared to those which had the LacZ control added instead. This suggests SMAD4 has a significant role in inhibiting metastatic colonization. b) The experiment is designed to find which of the genes transcriptionally regulated by SMAD4 can be either upregulated (if normally suppressed) or knocked out (if normally activated) in a cancer cell lines with functional SMAD4 to produce the highly metastatic phenotype of a SMAD4 knockout line.

Discovering the Genetic Mechanism of Enhanced Metastatic Colonization in SMAD4 Mutant Tumors

Pancreatic ductal adenocarcinomas (PDA) are a common but deadly form of cancer, with long-term survival made unlikely by the high rate of metastasis found in these tumors. At the time of diagnosis, a vast majority of PDA cases can no longer be sufficiently eliminated by surgery, and thus targeted nanoparticle therapies are a promising route of treatment. Identification of and drug delivery to highly metastatic cells via nanoparticles could greatly aid the long-term prognosis of patients, however first we have to understand what to target. The progression of PDA is often dependent upon the oncogenic activation of KRAS as well as the loss of the tumor suppressors CDKN2A, TP53, and SMAD4. SMAD4 is involved in TGFβ signaling pathways, and has a correlation with increased metastasis in cases where it is mutated or lost, making it of interest as a genetic source of PDA’s lethality. This metastatic dependence on SMAD4 dysfunction was confirmed by the very low rate of lung metastasis seen in mice after tail injection with SMAD4-/- pancreatic cancer cells reconstituted with functional SMAD4 as compared to the LacZ control (Figure a). A meta-analysis of the transcriptional targets of SMAD4 in PDA cell lines revealed hundreds of candidate genes, many of which have previously been implicated in metastasis. In an attempt to more specifically target these genes, an in vivo selection assay was used to find individual genetic “hits” that would increase the metastatic potential of isogenic cell lines dependent on SMAD4 for metastasis suppression (Figure b). Genes that SMAD4 normally upregulates were knocked out via CRISPR/Cas9, while genes that SMAD4 normally downregulates were overexpressed using a barcoded open reading frame (ORF) library. The sgRNA or ORF barcodes most prevalent in the lung metastases thus represent the hits which are genetically capable of increasing the metastatic ability of these cells. The results of this screen will be followed by further investigation of the most promising hits, especially those with previously documented presence in PDA patients or that affect a phenotype logically connected to metastasis. While initial screens were conducted using human cells in murine models, syngeneic murine models will be used to reveal interactions between this metastatic phenotype and immune response. Long-term results could then be used for targeted therapies involving nanoparticles to seek out and deliver therapies to the highly metastatic members of a PDA tumor population even after the cells have spread.

 

 

Trainee Research

CaNCURE provides trainees with a 6-month hands-on research experience and one-on-one mentoring by leading researchers in cancer nanomedicine.   Projects performed by current and past participants include:

Granzyme B Peptide as a Non-invasive Theranostic Agent

Characterization of Targeted PARP-inhibitor Nanoformulations In Vitro and In Vivo

Identifying genomic and compound dependencies in undifferentiated sarcomas

Assessment of atherosclerotic changes following neoadjuvant therapy using ferumoxytol as contrast imaging agent

Quantitative Multimodal Imaging of Tumor Response to Radiation

Radiation enhancement in cancer cells using gold and gadolinium nanoparticles

Discovering the Genetic Mechanism of Enhanced Metastatic Colonization in SMAD4 Mutant Tumors

Investigating the use of iron chelator deferoxamine (DFO)-bearing PEG-like nanoprobes as a multifunctional agent for cancer therapy and PET imaging

Evaluation of deep learning approaches in an integrated PET/MRI scanner to generate pelvis attenuation maps and characterize prostate cancer

Quantification of SPION accumulation in tumors using positive-contrast MRI

Combined Cisplatin and Olaparib nanoparticles for ovarian cancer therapy

Metabolite Quantification from Cancer Tissues using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging

Targeting WASp using Wiskostatin-gold nanoparticles

Localized chemo- and chemo-radiation for the treatment of prostate cancer

The Assessment and Comparison of Ferumoxtran as Contrast Imaging Agent in Patients with Pancreatic Cancers.

Development of PSMA-targeting nanoparticles for positron emitting tomography imaging in prostate cancer using animal models

Co-delivery of protective substrate and chemotherapy drugs via lipid Bilayer Mesoporous Silica Nanoparticles

Characterization of Nano-Dinaciclib in Combination with Nano-Talazoparib for the Treatment of Breast Cancer

Uptake and localization of nanoparticles in prostate and lung cancer cells as a function of time and nanoparticle type

Use of a Triblock Copolymer Hydrogel for Controlled Release of Cisplatin and BMN-673

Nanoparticle-aided radio-immunotherapy

Tracking pancreatic adenocarcinoma response to treatment using targeted, multi-modal nanoparticles

Using smart biomaterials with immunoadjuvants to treat metastatic breast cancer

Implementation of novel MR-based attenuation correction in PET/MR pelvic scans

Surface-targeting, ligand-switching nanoparticles for mitochondrial drug delivery in prostate cancer

Soleil Doggett (Biology, '16) talks to her fellow peers about her research on oxygenating tumors to stimulate the anti-tumor immune response.

 

Trainee e-portfolios

Photo credit: Tom Kates Photography

While on co-op, trainees document their research in an e-portfolio.  This gives trainees the opportunity to provide regular updates on their research progress, reflect on training they are receiving, and explain how their research fits within the field of cancer nanomedicine.  These research e-portfolios can be accessed through individual trainee profiles.  The complete collection may be found here.

 

Presentation at CaNCURE Nanomedicine Day

At the completion of their co-op, trainees are provided with the opportunity to present their research to a wider audience.  For our June CaNCURE Nanomedicine Day, trainees prepare interactive, digital posters to display on electronic poster boards.  Over 100 faculty, students, and researchers attend this annual event!

Check out the news article about our first CaNCURE Day!

Trainee Publications

Our Trainees have published 22 peer-reviewed since January 2015.  A full list of Trainee publications is found below.

  1. Patrick Sheedy, Zdravka Medarova. The fundamental role of miR-10b in metastatic cancer. Am J Cancer Res 2018;8(9):1674-1688. Link
  2. Chen X, Ling X, Zhao L, Xiong F, Hollett G, Kang Y, Barrett A, Wu J. “Biomimetic Shells Endow Sub-50 nm Nanoparticles with Ultrahigh Paclitaxel Payloads for Specific and Robust Chemotherapy.”  ACS Appl Mater Interfaces. 2018 Sep 25. doi: 10.1021/acsami.8b11571. PMID: 30203956  Link
  3. Hedgire S, Krebill C, Wojtkiewicz GR, Oliveira I, Ghoshhajra BB, Hoffmann U, Harisinghani MG. “Ultrasmall superparamagnetic iron oxide nanoparticle uptake as noninvasive marker of aortic wall inflammation on MRI: proof of concept study.”   Br J Radiol. 2018 Sep 12:20180461. doi: 10.1259/bjr.20180461. PMID: 30160173  Link
  4. Application of the BLADE Sequence in Upper Abdominal MR Imaging. Krebill C.  Radiol Technol. 2018 May;89(5):495-497. PMID:29793909 Link
  5. Torrado-Carvajal A, Vera-Olmos J, Izquierdo-Garcia D1, Catalano OA, Morales MA, Margolin J, Soricelli A, Salvatore M, Malpica N, Catana C1. Dixon-VIBE Deep Learning (DIVIDE) Pseudo-CT Synthesis for Pelvis PET/MR Attenuation Correction. J Nucl Med. 2018 Aug 30. pii: jnumed.118.209288. doi: 10.2967/jnumed.118.209288. PMID: 30166357  Link
  6. Xiaoyuan Ji, Jie Wang, Lin Mei, Wei Tao, Austin Barrett, Zhiguo Su, Shaomin Wang. Guanghui Ma, Jinjun Shi, Songping Zhang. Artificial Photosynthesis: Porphyrin/SiO2 /Cp*Rh(bpy)Cl Hybrid Nanoparticles Mimicking Chloroplast with Enhanced Electronic Energy Transfer for Biocatalyzed Artificial Photosynthesis. Advanced Functional Materials. Link
  7. Yang KS, Im H, Hong S, Pergolini I, Del Castillo AF, Wang R, Clardy S, Huang CH, Craig Pille, Ferrone, Yang R, Castro CM, Lee H, Del Castillo CF, Weissleder R. Multiparametric plasma EV profiling facilitates diagnosis of pancreatic malignancy. Sci Transl Med. 2017; 9(391): eaal3226. PMC5846089
  8. Zhu X, Ji X, Kong N, Chen Y, Mahmoudi M, Xu X, Ding L, Tao W, Cai T, Li Y, Gan T, Austin Barrett, Bharwani Z, Chen H, Farokhzad OC. Intracellular Mechanistic Understanding of 2D MoS2 Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy.  ACS Nano. 2018 Mar 27;12(3):2922-2938. PMC6097229
  9. Miller MA1, Kim E, Cuccarese MF, Alec Plotkin, Prytyskach M, Kohler RH, Pittet MJ, Weissleder R. “Near infrared imaging of Mer tyrosine kinase (MERTK) using MERi-SiR reveals tumor associated macrophage uptake in metastatic disease.” Chem Commun. 2017 Dec 19;54(1):42-45. PMC5736449
  10. Ding L, Zhu X, Wang Y, Shi B, Ling X, Chen H, Nan W, Austin Barrett, Guo Z, Tao W, Wu J, Shi X. “Intracellular Fate of Nanoparticles with Polydopamine Surface Engineering and a Novel Strategy for Exocytosis-Inhibiting, Lysosome Impairment-Based Cancer Therapy”. Nano Lett. 2017 Nov 8;17(11):6790-6801.  PMC6071871
  11. Yoo B, Ann-Marie, Billig, Medarova Z. “Guidelines for Rational Cancer Therapeutics. Frontiers in Oncology Journal”. Front Oncol. 2017 Dec 12;7:310. PMC5732930
  12. Gharagouzloo C, Timms L, Qiao J, Fang Z, Joseph Nneji, Pandya A, Kulkarni P, van de Ven AL, Ferris C, Sridhar S. “Neural circuits and brain function: New insights using quantitative vascular mapping of the rat.” Neuroimage, 2017. 16C:24-33  PMC5824692
  13. Gharagouzloo C, Timms L, Qiao J, Fang Z, Joseph Nneji, Pandya A, Kulkarni P, van de Ven AL, Ferris C, Sridhar S.   “Dataset on a 173 region awake resting state quantitative cerebral blood volume rat brain atlas and regional changes to cerebral blood volume under isoflurane anesthetization and CO2 challenge”. Data in Brief, 2018. 17:393-396.  Link
  14. Qin L, Li A, Qu J, Reinshagen K, Li X, Cheng S, Annie Bryant, Young GS. Normalization of ADC does not improve correlation with overall survival in patients with high-grade glioma (HGG). J Neurooncol. 2018 Apr;137(2):313-319.   PMC6071871
  15. Belz J, Kumar R, Baldwin P, Noelle Castilla Ojo, Leal AS, Royce DB, Di Zhang D, van de Ven AL, Liby K, Sridhar S. “Sustained-release Talazoparib implants for localized treatment of BRCA1-deficient breast cancer”. Theranostics, 7(17): 4340-4349.  PMC5695017
  16. Qin L, Li X, Amanda Stroiney, Qu J, Helgager J, Reardon DA, Young GS. “Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma.” 2017 Feb;59(2):135-145.  PMC6097616
  17. Jodi Belz, Noelle Castilla Ojo,Srinivas Sridhar, Rajiv Kumar.  Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer, In Cancer Nanotechnology. Reema Zeineldin (Ed).  Series: Methods in Molecular Biology. Springer Press. Methods Mol Biol. 2017; 1530:403-409. PMC5531609
  18. Christian Berrios, Megha Padi, Mark A. Keibler, Donglim Esther Park, Vadim Molla, Gregory Stephanopoulos, John Quackenbush, James A. DeCaprio. “Merkel cell polyomavirus small T antigen promotes pro-glycolytic metabolic perturbations required for transformation”. 2016 Nov 23;12(11):e1006020.   PMC5120958
  19. Song C, Liu Y, Rachel Fontana, Makrigiorgos A, Mamon H, Kulke MH, G. Mike Makrigiorgos. “Elimination of unaltered DNA in mixed clinical samples via nuclease-assisted minor-allele enrichment”.  2016 Nov 2;44(19):e146. PMC5100565
  20. Andrew L. Hong, Yuen-Yi Tseng, Glenn S. Cowley, Oliver Jonas, Jaime H. Cheah, Bryan D. Kynnap, Mihir B. Doshi, Coyin Oh, Stephanie C. Meyer, Alanna J. Church, Shubhroz Gill, Craig M. Bielski, Paula Keskula, Alma Imamovic, Sara Howell, Gregory V. Kryukov, Paul A. Clemons, Aviad Tsherniak, Francisca Vazquez, Brian D. Crompton, Alykhan F. Shamji, Carlos Rodriguez-Galindo, Katherine A. Janeway, Charles W. M. Roberts, Kimberly Stegmaier, Paul van Hummelen,
Michael J. Cima, Robert S. Langer, Levi A. Garraway, Stuart L. Schreiber, David E. Root,
William C. Hahn, & Jesse S. Boehm. “Integrated genetic and pharmacologic interrogation of rare cancers”. Nat Commun. 2016 Jun 22;7:11987.  PMC4917959
  21. Wang P, Yoo B, Sherman S, Mukherjee P, Ross A, Pantazopoulos P, Petkova V, Farrar C, Medarova Z, Moore A. “Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer.” Int J Cancer. 2016 Aug 1;139(3):712-8. PMCID: PMC4925171
  22. Nazila Kamaly, Gabrielle Fredman, Jhalique J. Fojas, Manikandan Subramanian, Won II Choi, Katherine Zepeda, Cristian Vilos, Mikyung Yu, Suresh Gadde, Jun Wu, Jaclyn Milton, Renata Leitao, Livia Rosa, Moaraj Hasan, Huayi Gao, Vance Nguyen, Jordan Harris, Ira Tabas, and Omid C. Farokhzad. “Interleukin-10 Targeted Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis”. ACS Nano. 2016 May 24;10(5):5280-92. PMC5199136