Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.226282v1?rss=1

Authors: Zhang, S. M., Calderon-Montano, J. M., Rudd, S. G.

Abstract:

Oncogenes induce DNA replication stress in cancer cells. Although this was established more than a decade ago, we are still unravelling the molecular underpinnings of this phenomenon, which will be critical if we are to exploit this knowledge to improve cancer treatment. A key mediator of oncogene-induced replication stress is the availability of DNA precursors, which will limit ongoing DNA synthesis by cellular replicases. In this study, we identify a potential role for nucleotide catabolism in promoting replication stress induced by oncogenes. Specifically, we establish that the dNTPase SAMHD1 slows DNA replication fork speeds in human fibroblasts harbouring an oncogenic RAS allele, elevating levels of endogenous DNA damage, and ultimately limiting cell proliferation. We then show that oncogenic RAS-driven tumours express reduced SAMHD1 levels, suggesting they have overcome this tumour suppressor barrier, and that this correlates with worse overall survival for these patients.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.28.224253v1?rss=1

Authors: Komura, D., Kawabe, A., Fukuta, K., Sano, K., Umezaki, T., Koda, H., Suzuki, R., Tominaga, K., Konishi, H., Nishida, S., Furuya, G., Katoh, H., Ushiku, T., Fukayama, M., Ishikawa, S.

Abstract:

Cancer histological images contain rich biological and clinical information, but quantitative representation can be problematic and has prevented direct comparison and accumulation of large-scale datasets. Here we show that deep texture representations (DTRs) produced by a bilinear Convolutional Neural Network, express cancer morphology well in an unsupervised manner, and work as a universal encoder for cancer histology. DTRs are useful for content-based image retrieval, enabling quick retrieval of histologically similar images from optimally area selected datasets of 7,175 cases from The Cancer Genome Atlas. Via comprehensive comparison with driver and clinically actionable gene mutations, we have successfully predicted 309 combinations of genomic features and cancer types from hematoxylin and eosin-stained images at high accuracy (AUC > 0.70 and q < 0.02). With its mounting capabilities on accessible devices such as smartphones, DTR-based encoding for cancer histology has a potentially strong impact on global equalization for cancer diagnosis and targeted therapies.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.226274v1?rss=1

Authors: Prakash, O.

Abstract:

Present study deals with theoretical analysis of multi-tissue RNA expressions through system model based network mapping under the constraints of in-vitro experiments. Here, effect of Neuroligin was evaluated on the performance of metastatic behavior of CD66+ cells of human female reproductive cell lines. Total 10 genes and 14 cell lines were considered in the study. Clustering of cell lines was done on the basis of network mapping under the same homeostatic constraints. Neuroligin was found to affect metastatic performance of CD66+ cells. Two CD66+ cell lines hTERT-HME1 and SK-BR-3 were found to most effective, in similar manner as brain cell lines as U-138MG & U-87MG.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.28.220343v1?rss=1

Authors: Khan, S., Shin, J. H., Ferri, V., Cheng, N., Noel, J. E., Kuo, C., Sunwoo, J. B., Pratx, G.

Abstract:

Organoid tumor models have found application in a growing array of cancer studies due to their ability to closely recapitulate the structural and functional characteristics of solid tumors. However, organoids are too small to be compatible with common radiological tools used in oncology clinics. Here, we present a microscopy method to image 18F-fluorodeoxyglucose in patient-derived tumor organoids with spatial resolution up to 100-fold better than that of clinical positron emission tomography (PET). When combined with brightfield imaging, this metabolic imaging approach functionally mirrors clinical PET/CT scans and provides a quantitative readout of cell glycolysis. In particular, the specific avidity of a tumor for FDG, or lack thereof, was maintained when the tumor cells were grown ex vivo as tumor organoids. In addition, cisplatin treatment caused a dose-dependent decrease in the metabolic activity of these organoids, with the exception of one patient whose tumor was also resistant to cisplatin treatment. Thus, FDG-imaging of organoids could be used to predict the response of individual patients to different treatments and provide a more personalized approach to cancer care.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.218248v1?rss=1

Authors: Carta, L., Hutcheson, R., Davis, S. A., Rudolph, M. J., Reynolds, C. H., Quick, M., Williams, T. M., Schmertzler, M., Hadari, Y. R.

Abstract:

RAS genes encode small GTPases essential for proliferation, differentiation, and survival of mammalian cells. RAS gene mutations are associated with approximately 30% of all human cancers. However, based on measurements reported three decades ago of Ras protein affinities to GTP in the 10-20 picomolar range, it has been accepted in the scientific and medical communities that Ras proteins are undruggable targets. Here, we report MicroScale Thermophoresis and scintillation proximity assay measurements of the affinity of K-Ras and several K-Ras mutants for GTP in the range of 200 nanomolar, a 10,000-fold difference from that previously reported, and the identification of over 400 small molecules that block GTP binding to K-Ras. Focusing on two of those molecules, we report small molecule inhibition of Ras downstream signaling and cellular proliferation in human pancreatic and non-small cell lung cancer cells expressing wild type and K-Ras G12C, G12D and G12S, and N-Ras Q61K mutants.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.28.225813v1?rss=1

Authors: Lee, J. J., Bernard, V., Semaan, A., Monberg, M. E., Huang, J., Stephens, B. M., Lin, D., Weston, B. R., Bhutani, M. S., Haymaker, C. L., Bernatchez, C., Taniguchi, C. M., Maitra, A., Guerrero, P. A.

Abstract:

Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. However, the long-term fidelity of recently deployed ex vivo preclinical platforms, such as patient-derived organoids (PDOs) remains unknown. Through single-cell RNA sequencing (scRNA-seq), we identify substantial transcriptomic evolution of PDOs propagated from the parental tumor, which may alter predicted drug sensitivity. In contrast, scRNA-seq is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast (CAF) subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. While PDOs continue to enable prospective therapeutic prediction, our analysis also demonstrates the complementarity of using orthogonal de novo biopsies from PDAC patients paired with scRNA-seq to inform clinical decision-making.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.223834v1?rss=1

Authors: Inda, M. A., van Swinderen, P., van Brussel, A., Moelans, C. B., Veraheagh, W., van Zon, H., den Biezen-Timmermans, E. C., Bikker, J. W., van Diest, P. J., van de Stolpe, A.

Abstract:

Background: Targeted drug treatment aims to block tumor driving signaling pathways, and is generally based on analysis of one primary tumor (PT) biopsy. Phenotypic heterogeneity within primary and between primary and metastatic lesions was investigated. Methods: Activity of androgen and estrogen receptor, PI3K-FOXO, Hedgehog, TGFbeta, and Wnt signaling pathways was measured in breast cancer samples using a novel mRNA-based assay platform. Macro-scale heterogeneity analysis was performed on multiple spatially distributed PT tissue blocks from 17 luminal A-like, 9 luminal B-like, and 9 ER-negative primary breast cancers; micro-scale heterogeneity analysis was performed on four "quadrant" samples of a single tissue block of respectively 9, 4, and 4 matched PT. Samples from 6 PT with matched lymph node (LN, n=23) and 9 PT with distant metastatic sites (DS, n=12) were analyzed. Statistical variance analysis was performed with linear mixed models. A "checkerboard" model was introduced to explain the observed heterogeneity in PT. Results: Within PT, macro-scale heterogeneity in signaling pathway activity was similar to micro-scale heterogeneity, with a possible exception of the PI3K pathway. Variation was significantly higher on microscale for Hedgehog and TGFbeta pathways. While pathway activity scores correlated significantly between different locations in the PT, positive correlations decreased between PT and LN, and even more between PT and DS metastases, including the emergence of a negative correlation for the ER pathway. Conclusion: With a possible exception of the PI3K pathway, variation in signaling pathway activity within a single PT tissue block was generally representative for the whole PT, but not for DS or LN metastases. The higher variation in TGFbeta and HH pathway activity on microscale suggested the presence of multiple small cancer cell clones. While analysis of multiple sub-samples of a single biopsy block may be sufficient to predict PT response to some targeted therapies, such as hormonal therapy, metastatic breast cancer treatment requires analysis of metastatic biopsies. The findings on phenotypic intra-tumor heterogeneity are compatible with currently emerging ideas on a Big Bang type of cancer evolution.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.28.222927v1?rss=1

Authors: Xu, Z., Vandenberg, C., Lieschke, E., Scott, C. L., Majewski, I. J.

Abstract:

Cancer patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi) experience various side effects, with hematological toxicity being most common. Short term treatment of mice with olaparib resulted in depletion of reticulocytes, B cell progenitors and immature thymocytes, whereas longer treatment induced broader myelosuppression. We performed a CRISPR/Cas9 screen targeting DNA repair genes to identify strategies to suppress hematological toxicity. The screen revealed that sgRNAs targeting the serine/threonine kinase CHK2 were enriched following olaparib treatment. Genetic or pharmacological inhibition of CHK2 blunted PARPi response in lymphoid and myeloid cell lines, and in primary pre-B/pro-B cells. Using a Cas9 base editor, we found that blocking CHK2-mediated phosphorylation of p53 also impaired olaparib response. Our results identify the p53 pathway as a major determinant of the acute response to PARPi in normal blood cells and demonstrate that targeting CHK2 can short-circuit this response. Cotreatment with a CHK2 inhibitor did not antagonise olaparib response in ovarian cancer cells. Selective inhibition of CHK2 may spare blood cells from the toxic influence of PARPi and broaden the utility of these drugs.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.28.225763v1?rss=1

Authors: Cai, L., Liu, H., Huang, F., Fujimoto, J., Girard, L., Chen, J., Li, Y., Zhang, Y.-a., Deb, D., Stastny, V., Kuo, C. S., Jia, G., Yang, C., Zou, W., Aloma, A., Huffman, K., Papari-Zareei, M., Yang, L., Drapkin, B., Akbay, E., Shames, D. S., Wistuba, I. I., Wang, T., Xiao, G., DeBerardinis, R. J., Minna, J. D., Xie, Y., Gazdar, A. F.

Abstract:

Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed "variant" due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings provide a new framework to guide design of treatment regimens in SCLC.

Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.27.223529v1?rss=1

Authors: Grant, H., Zhang, Y., Li, L., Wang, Y., Kawamoto, S., Penisson, S., Fouladi, D. F., Shayesteh, S., Blanco, A., Ghandili, S., Zinreich, E., Graves, J. S., Park, S., Kern, S., Hooper, J., Yuille, A. L., Fishman, E. K., Chu, L., Tomasetti, C.

Abstract:

Obesity increases significantly cancer risk in various organs. Although this has been recognized for decades, the mechanism through which this happens has never been explained. Here, we show that obese people (BMI [≥]30) have on average 55% (95%CI: 46%-66%), 68% (95%CI: 59%-76%), and 39% (95%CI: 29%-49%) larger kidneys, liver, and pancreas, respectively. We also find a significant linear relationship between the increase in organ volume and the increase in cancer risk (P-value<10-12). These results provide a mechanism explaining why obese individuals have higher cancer risk in several organs: the larger the organ volume the more cells at risk of becoming cancerous. These findings are important for a better understanding of the effects that obesity has on cancer risk and, more generally, for the development of better preventive strategies to limit the mortality caused by obesity.

Copy rights belong to original authors. Visit the link for more info