Trans-Network Projects

To encourage collaboration across the Physical Sciences Oncology Network, the Physical Sciences Oncology Centers support an annual trans-network projects that leverage the expertise of multiple PS-OCs and/or PS-OPs to test or validate new ideas. To be eligible for these awards, network researchers must form multi-center teams that develop proposals to investigate these new ideas.

Trans-Network Projects Supported by the Chicago-Region Physical Sciences Oncology Center are as follows:

YEAR 01

The Role of Liver Stiffness and Portal Pressure in from Primary and Metastatic Cancer
Investigators: Andrew Mazar, PhD, Chicago Region PS-OC; Dennis Discher, PhD, University Pennsylvania PS-OC

Emergence of Tumor Heterogeneity: From Intra- To Inter-Cellular States
Investigators: Vadim Backman, PhD, Chicago Region PS-OC; Raul Rabadan, PhD and Antonio Iavarone, MD, Columbia University PS-OC

YEAR 02

Mechanobiological Control of Aneuploidy during Chromosome Segregation
Investigators: John Marko, PhD, Chicago Region PS-OC; Andrea J. Liu, PhD, University Pennsylvania PS-OC

 


YEAR 01

The Role of Liver Stiffness and Portal Pressure in from Primary and Metastatic Cancer

Investigators: Dennis Discher, PhD, University Pennsylvania PS-OC; Andrew Mazar, PhD Chicago Region PS-OC

Pancreatic adenocarcinoma (PDAC) is one of most aggressive and difficult to treat tumor types leading to an extremely high mortality rate. Primary PDAC tumors restricted to the pancreas are often highly fibrotic and difficult to treat due to primary drug resistance and impeded drug uptake and delivery to the tumor. Surgical resection of PDAC restricted to the pancreas modestly improves overall survival. However, 85-90% of patients diagnosed with PDAC are not eligible for surgery because they present with metastatic disease most often to the liver. Current therapeutic approaches to treating patients with metastatic PDAC are largely ineffective leading to a several month improvement in overall survival at best but the underlying reasons for the inability of current standard of care approaches to impact metastatic PDAC are poorly understood. One hypothesis is that PDAC that has metastasized to liver induces fibrosis and similar to primary PDAC, this fibrosis promotes metastatic PDAC progression by altering local tissue stiffness leading to changes in tumor gene expression and response to therapy. A recent study by Whatcott et al. demonstrated that clinical PDAC metastatic lesions in the liver were also characterized by desmoplasia and that extracellular matrix deposition of protein markers of desmoplasia such as collagen and hyaluronan were correlated with poor prognosis. However, there are currently no xenograft models that evaluate desmoplasia in PDAC metastasis or its role in the progression of this tumor type.

In this PS-ON trans-network proposal, we leverage the Northwestern (NU) PS-ON patient-derived xenograft (PDX) core, which has developed and continues to expand a repository of PDAC PDX models. The NU PS-ON PDX Core has developed tools and expertise in growing PDAC PDX subcutaneously (SC) to expand the amount of tumor available for studies; dissociating tumor for labeling with reporter constructs such as luciferase: establishing orthotopic models of PDAC PDX tumors using tumor suspensions or tumor fragments for engraftment; and generating early passage PDAC cell lines from these PDX tumors. Using established PDAC cell lines, the PDX Core has generated proof-of-concept models of PDAC metastasis using both intrahepatic and intrasplenic inoculation of tumor cells. However, these cell line-based PDAC metastasis models are not representative of human PDAC metastasis and differ substantially in their molecular profiles, histological appearance, and the lack of desmoplasia.

These models of metastatic PDAC desmoplasia will then be evaluated for alterations in liver stiffness in collaboration with Professor Dennis Discher and the University of Pennsylvania PS-OC. PDAC metastatic lesions that alter liver stiffness will then be assessed for changes in gene expression compared to parental PDX tumors grown SC. These PDX models provide a system where molecular and physical changes may be introduced to alter tumor stiffness. Thus, if this pilot is successful, the collaboration between the PS-ON transnetwork NU and Penn PS-ON will generate a platform that will be used to assess changes in PDAC metastatic lesion stiffness, gene expression, drug sensitivity, and drug delivery. 

Emergence of Tumor Heterogeneity: From Intra- to Inter-Cellular States

Investigators: Vadim Backman, PhD, Chicago Region PS-OC; Raul Rabadan, PhD and Antonio Iavarone, MD, Columbia University PS-OC

Development of tumor heterogeneity is a crucial hallmark of carcinogenesis that has been shown to be associated with tumor aggressiveness and therapy resistance. Tumors are comprised of genetically, epigenetically, metabolically and, in general, phenotypically-distinct cancer cells, and the heterogeneity of human tumors crosses all these scales. This is particularly true in many solid tumors including glioblastomas (GBM), the most common and aggressive primary brain tumor. These tumors are highly heterogeneous at the mutational level, showing highly branched evolutionary patterns in which 61% of patients experience expression-based subtype changes.

Raul Rabadan and Antonio Iavarone, Columbia University PSOC, will study the role of inter-cellular heterogeneity in cancer progression and therapy resistance in glioblastomas. Vadim Backman, Chicago-area PSOC, will study the role of intra-cellular (chromatin and genomic) heterogeneity above the nucleosomal level (20-200 nm) as a key event in early carcinogenesis using a novel nanoscale-sensitive biophotonics technology, nanocytometry. The project will leverage the methods of bioengineering, computational genomics and molecular biology.

 


YEAR 02

Mechanobiological Control of Aneuploidy during Chromosome Segregation

Investigators: John Marko, PhD, Chicago Region PS-OC; Andrea J. Liu, PhD, University Pennsylvania PS-OC

Chromosomal instability (CIN) is one of the major hallmarks of cancer. However, the role and mechanisms of chromosomal number variation, or aneuploidy, is less understood than intrachromosomal variability that arises from insertions, deletions and mutations. Interestingly, aneuploidy is exceptionally common in nearly all cancers and also correlates significantly with cancerous pre-disposition. Since aneuploidy is expected to arise during cell division, understanding the biophysical and molecular mechanisms that cause aneuploidy during chromosome segregation will provide insight into CIN.

To address these questions of how mechanical factors can drive aneuploidy, this project combines expertise from the Marko (NU) group on chromosomal structure and mechanics and the Liu group (UPenn) on the role of mechanics in cell biology on subcellular to tissue scales. We will develop theoretical models of the mitotic spindle that incorporate key chromosome-MT mechanics and dynamics. The first aim of the proposed research builds upon a previous collaboration between NU and UPenn, in order to develop a theoretical/computational model of spindle K fiber dynamics and mechanics that can accurately describe mechanobiological mechanisms of aneuploidy during mitosis. The second aim is to theoretically understand the effects of microenvironment mechanics on the structure and dynamics of the mitotic spindle using a quantitatively accurate active liquid crystal model.