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1. Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

   https://doi.org/10.1158/1078-0432.CCR-23-0131  

   Roy Chaudhuri, Tista; Lin, Qingxiang; Stachowiak, Ewa K.; Rosario, Spencer R.; Spernyak, Joseph A.; Ma, Wen Wee; Stachowiak, Michal K.; Greene, Michelle K.; Quinn, Gerard P.; McDade, Simon S.; et al (January 2024, Clinical Cancer Research)

   Abstract Purpose: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) ‘primes’ PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them, and devise approaches to stratify SHHi-responsive tumors non-invasively based on clinically-quantifiable parameters. Experimental design: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intra-tumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key ‘nodes’ responsible for EMT induction. Results: multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Non-responding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. Conclusion: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification. 

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2. An image-based modeling framework for predicting spatiotemporal brain cancer biology within individual patients

   https://doi.org/10.3389/fonc.2023.1185738  

   Bond, Kamila M; Curtin, Lee; Ranjbar, Sara; Afshari, Ariana E; Hu, Leland S; Rubin, Joshua B; Swanson, Kristin R (October 2023, Frontiers in Oncology)

   Imaging is central to the clinical surveillance of brain tumors yet it provides limited insight into a tumor’s underlying biology. Machine learning and other mathematical modeling approaches can leverage paired magnetic resonance images and image-localized tissue samples to predict almost any characteristic of a tumor. Image-based modeling takes advantage of the spatial resolution of routine clinical scans and can be applied to measure biological differences within a tumor, changes over time, as well as the variance between patients. This approach is non-invasive and circumvents the intrinsic challenges of inter- and intratumoral heterogeneity that have historically hindered the complete assessment of tumor biology and treatment responsiveness. It can also reveal tumor characteristics that may guide both surgical and medical decision-making in real-time. Here we describe a general framework for the acquisition of image-localized biopsies and the construction of spatiotemporal radiomics models, as well as case examples of how this approach may be used to address clinically relevant questions. 

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3. Primary Human Breast Cancer‐Associated Endothelial Cells Favor Interactions with Nanomedicines

   https://doi.org/10.1002/adma.202403986  

   Wang, Lin; Sheth, Vinit; Liu, Kaili; Panja, Prasanta; Frickenstein, Alex_N; He, Yuxin; Yang, Wen; Thomas, Abigail_G; Jamei, Mohammad_Hasan; Park, Jeesoo; et al (May 2024, Advanced Materials)

   Abstract Cancer nanomedicines predominately rely on transport processes controlled by tumor‐associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor‐associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer‐associated endothelial cells exhibit up to ≈2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super‐resolution imaging studies reveal a significantly higher intracellular vesicle number for tumor‐associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicate the upregulation of transport‐related genes, especially motor protein genes, in tumor‐associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer‐associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cells in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor‐associated endothelial cell‐mediated transport into human solid tumors may lead to the development of safer and more effective clinical cancer nanomedicines. 

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4. Abstract 4567: Transcriptomic analysis of a 3D engineered cancer model recapitulating stage-dependent heterogeneity in colorectal PDX tumors

   https://doi.org/10.1158/1538-7445.AM2023-4567  

   Tian, Yuan; Hassani, Iman; Anbiah, Benjamin; Ahmed, Bulbul; Van_Der_Pol, William; Lefkowitz, Elliot J; Kuhlers, Peyton C; Habbit, Nicole L; Heslin, Martin J; Lipke, Elizabeth A; et al (April 2023, Cancer Research)

   Colorectal cancer (CRC) is the third-most leading cause of cancer-related deaths in the United States. To advance the understanding of CRC tumor progression, models which mimic the tumor microenvironment (TME) and have translatable study outcomes are urgently needed. CRC patient-derived xenografts (PDXs) are promising tools for their ability to recapitulate tumor heterogeneity and key patient tumor characteristics, such as molecular characteristics. However, as in vivo models, CRC PDXs are costly and low-throughput, which leads to a need for equivalent in vitro models. To address this need, we previously established an in vitro model using a tissue engineering toolset with CRC PDX cells. However, it is unclear whether tissue engineering has the capacity to maintain patient- and/or cancer stage-specific tumor heterogeneity. To address this gap, we employed three PDX tumor lines, originated from stage II, III-B, and IV CRC tumors, in the formation of 3D engineered CRC PDX (3D-eCRC-PDX) tissues and performed an in-depth comparison between the 3D-eCRC-PDX tissues and the original CRC-PDX tumors. To form the tissues, CRC-PDX tumors were expanded in vivo and dissociated. The isolated cells were encapsulated within poly(ethylene glycol)-fibrinogen hydrogels and remained viable and proliferative post encapsulation over the course of 29 days in culture. To gain molecular insight into the maintenance of PDX line stage heterogeneity, we performed a transcriptomic analysis using RNA seq to determine the extent to which there were similarities and differences between the CRC-PDX tumors and the 3D-eCRC-PDX tissues. We observed the greatest correspondence in overlapping differentially expressed human genes, gene ontology, and Hallmark gene set enrichment between the 3D-eCRC-PDX tissues and CRC-PDX tumors in the stage II PDX line, while the least correspondence was observed in the stage IV PDX line. The Hallmark gene set enrichment from murine mapped RNA seq transcripts was PDX line-specific which suggested that the stromal component of the 3D-eCRC-PDX tissues was maintained in a PDX line-dependent manner. Consistent with our transcriptomic analysis, we observed that tumor cell subpopulations, including human proliferative (B2M+Ki67+) and CK20+ cells, remained constant for up to 15 days in culture even though the number of cells in the 3D-eCRC-PDX tissues from all three CRC stages increased over time. Yet, tumor cell subpopulation differences in the stage IV 3D-eCRC-PDX tissues were observed starting at 22 days in culture. Overall, our results demonstrate a strong correlation between our in vitro 3D-eCRC-PDX models and the originating in vivo CRC-PDX tumors, providing evidence that these engineered tissues may be capable of mimicking patient- and/or cancer stage-specific heterogeneity. 

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5. Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety

   https://doi.org/10.1039/d0lc00424c  

   Chramiec, Alan; Teles, Diogo; Yeager, Keith; Marturano-Kruik, Alessandro; Pak, Joseph; Chen, Timothy; Hao, Luke; Wang, Miranda; Lock, Roberta; Tavakol, Daniel Naveed; et al (November 2020, Lab on a Chip)

   Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease, motivating the development of microfluidic organs-on-a-chip (OOC) platforms that can mimic many aspects of human physiology and in the process alleviate many of the discrepancies between preclinical studies and clinical trials outcomes. Linsitinib, a novel anti-cancer drug, showed promising results in pre-clinical models of Ewing Sarcoma (ES), where it suppressed tumor growth. However, a Phase II clinical trial in several European centers with patients showed relapsed and/or refractory ES. We report an integrated, open setting, imaging and sampling accessible, polysulfone-based platform, featuring minimal hydrophobic compound binding. Two bioengineered human tissues – bone ES tumor and heart muscle – were cultured either in isolation or in the integrated platform and subjected to a clinically used linsitinib dosage. The measured anti-tumor efficacy and cardiotoxicity were compared with the results observed in the clinical trial. Only the engineered tumor tissues, and not monolayers, recapitulated the bone microenvironment pathways targeted by linsitinib, and the clinically-relevant differences in drug responses between non-metastatic and metastatic ES tumors. The responses of non-metastatic ES tumor tissues and heart muscle to linsitinib were much closer to those observed in the clinical trial for tissues cultured in an integrated setting than for tissues cultured in isolation. Drug treatment of isolated tissues resulted in significant decreases in tumor viability and cardiac function. Meanwhile, drug treatment in an integrated setting showed poor tumor response and less cardiotoxicity, which matched the results of the clinical trial. Overall, the integration of engineered human tumor and cardiac tissues in the integrated platform improved the predictive accuracy for both the direct and off-target effects of linsitinib. The proposed approach could be readily extended to other drugs and tissue systems. 

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