Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.03.232561v1?rss=1

Authors: Lai, T.-h., Ozer, H. G., Gasparini, P., Giovanni, N., Destafano, R., Ravikrishnan, J., Tsai, T.-l., Lapalombella, R., Woyach, J., Puduvalli, V., Blachly, J., Byrd, J. C., Sampath, D.

Abstract:

HDAC1 is a key regulator of gene expression in cancer. We identified a critical role for HDAC1 in establishing the transcriptional dependencies essential for survival in chronic lymphocytic leukemia (CLL) by profiling HDAC1 with BRD4, H3K27Ac superenhancers, H4K9Ac, chromatin accessibility signatures, Pol2 measurements and expression signatures to generate a regulatory chromatin landscape. Superenhancers marked by high levels of acetylation and BRD4 paradoxically also recruited the highest levels of HDAC1. HDAC inhibition poisoned transcription at these loci to selectively disrupt B-cell transcription factors and B-cell receptor signaling. HDAC1 was also recruited genome-wide at promoters without superenhancers to repress expression; HDAC inhibition reverses silencing at these loci, which include key microRNA networks that reciprocally downregulate CLL specific survival and driver genes. Our work provides a compelling rationale for profiling HDAC1 across cancers to characterize its role in driving transcriptional dysregulation that is a hallmark of most cancers and develop epigenetic therapeutic strategies.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.31.231001v1?rss=1

Authors: Sano, Y., Yoshida, T., Choo, M.-K., Jimenez-Andrade, Y., Hill, K. R., Georgopoulos, K., Park, J. M.

Abstract:

Hematopoietic-derived cells are integral components of the tumor microenvironment and serve as critical mediators of tumor-host interactions. Cells derived from myeloid and lymphoid lineages perform well-established functions linked to cancer development, progression and response to therapy. It is unclear whether erythroid cells exert such host cell functions in cancer, but emerging evidence points to this possibility. Here we show that tumor-promoting environmental stress and tumor-induced physiological disruption trigger renal erythropoietin production and erythropoietin-dependent expansion of splenic erythroid cell populations in mice. These erythroid cells display molecular features indicative of an immature erythroid phenotype and express immune checkpoint molecules. Erythroid cells with similar properties are present in mouse and human tumor tissues. Antibody-mediated erythropoietin blockade or erythroid cell depletion reduces tumor growth. These findings reveal the potential of erythropoietin and erythroid cells as targets for cancer treatment.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.228676v1?rss=1

Authors: li, s., Ye, Y., Wang, J.-j.

Abstract:

We would like to submit an original article entitled "miR-100-5p downregulates mTOR to suppress the proliferation, migration and invasion of prostate cancer cells" from Su-Liang Li for consideration for publication in "Plos One".

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.31.230300v1?rss=1

Authors: Arnaiz, E., Miar, A., Dias, A. G., Prasad, N., Schulze, U., Waithe, D., Rehwinkel, J., Harris, A. L.

Abstract:

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This was HIF1/2-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reaveal a mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.227561v1?rss=1

Authors: Stires, H., Olukoya, A. O., Ma, S., Persaud, S., Guerra, Y., Cruz, M. I., Benitez, C., Rozeboom, A., Ceuleers, H., Berry, D. L., Jacobsen, B. M., Raj, G. V., Riggins, R. B.

Abstract:

Background . Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. In several (but not all) of these studies, Riluzole-mediated growth inhibition is attributed to increased expression of metabotropic glutamate receptors (mGluRs, GRMs). We recently reported that acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole. Methods . In the current study, we tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1 -mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI. Results . Single-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro , inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). In an invasive lobular, endocrine resistant model, Riluzole induced apoptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole in combination with either Fulvestrant or 4-hydroxytamoxifen additively or synergistically suppressed ER+ breast cancer cell growth in vitro . The combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures, and inhibited HCI-013EI xenograft growth in vivo significantly earlier than Fulvestrant alone. Conclusions . These findings suggest Riluzole combined with endocrine therapy may offer therapeutic benefit in diverse ER+ breast cancers, including lobular breast cancer.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.226654v1?rss=1

Authors: Pradhan, T., Panchal, V., H, E. S., R, K., John, S., T, J. V., S, A., K, C., NAIR, S. A.

Abstract:

Discovery of potent genes regulating tumorigenesis and drug resistance is of high clinical importance. STIL is an oncogene, however its molecular insights and role in colorectal oncogenesis are unknown. In this study we have explored role of STIL in tumorigenesis and studied its molecular targets in colorectal cancer (CRC). STIL silencing reduced proliferation and tumor growth in CRC. Further, STIL was found to regulate stemness markers CD133 & CD44 and drug resistant markers Thymidylate synthase, ABCB1 & ABCG2 both in in-vitro and in-vivo CRC models. In addition, over expression of STIL mRNA was found to be associated with reduced disease free survival in CRC cases. To our surprise we observed an Shh independent regulation of stemness and drug resistant genes mediated by STIL. Interestingly, we found an Shh independent regulation of {beta}-catenin mediated by STIL via p-AKT, which partially answers Shh independent regulatory mechanism of CSC markers by STIL. Our study suggest an instrumental role of STIL in molecular manifestation of CRC and progression.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.223925v1?rss=1

Authors: Kokkinos, J., Sharbeen, G., Haghighi, K. S., Ignacio, R. M. C., Kopecky, C., Gonzales-Aloy, E., Youkhana, J., Pandzic, E., Boyer, C., Davis, T. P., Butler, L. M., Goldstein, D., McCarroll, J. A., Phillips, P. A.

Abstract:

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to the highly fibrotic stroma and complex multi-cellular microenvironment that is difficult to fully recapitulate in pre-clinical human models. To fast-track translation of therapies and to inform personalised medicine, we aimed to develop a whole-tissue ex vivo explant model that maintains viability, 3D multicellular architecture, and microenvironmental cues present in human pancreatic tumours. Patient-derived surgically-resected PDAC tissue was cut into 2 mm explants, cultured on gelatin sponges, and grown for 12 days. Immunohistochemistry revealed that human PDAC tissue explants were viable for 12 days and maintained their original tumour, stromal and extracellular matrix architecture. As proof-of-principle, human PDAC tissue explants responded to Abraxane(R) treatment with a 3.7-fold increase in cell-death (p=0.0007). PDAC explants were also transfected with polymeric nanoparticles+Cy5-siRNA and we observed abundant cytoplasmic distribution of nanoparticle+Cy5-siRNA throughout the PDAC explant tissue. Our novel model retains the 3D architecture of human pancreatic tumours and has several advantages over standard organoids: presence of functional multi-cellular stroma and fibrosis and no tissue manipulation, digestion, or artificial propagation of organoids. This provides an unprecedented opportunity to study PDAC biology, tumour-stromal interactions and rapidly assess therapeutic response that could drive personalised treatment for PDAC.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.29.227454v1?rss=1

Authors: Tung, H.-R., Durrett, R.

Abstract:

We investigate the site frequency spectrum in the two-type model of clonal evolution. If the fitnesses of the two types are {lambda}_0<{lambda}_1 then the site frequency spectrum is c/f^ where ={lambda}_0/{lambda}_1. This is due to the advantageous mutations that produce the founders of the type 1 population. Mutations within the growing type 0 and type 1 populations follow the 1/f law. Our results show that neutral evolution can be distinguished from the two-type model using the site frequency spectrum.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.228445v1?rss=1

Authors: Chakladar, M., Nair, M., Prabhu, J., Sridhar, T., Kelkar, D., Kulkarni, M., SHASHIDHARA, L.

Abstract:

PTPN11/SHP2, a non-receptor protein tyrosine phosphatase is a prominent target of the receptor tyrosine kinase that participates in positive feedback signalling of the human epidermal growth factor receptors and helps in growth and migration. PTPN11/SHP2 is widely believed to be an oncoprotein, although its possible tumor-suppressor role is also reported. Our analysis of breast cancer metadata shows, PTPN11/SHP2 copy number loss in luminal A subtype is correlated to poor disease-specific survival and late-stage cancer at diagnosis. Analysis of the level 4 Reverse Phase Protein Array (RPPA) data available on the TCGA database resulted in positive correlations between the lower expression levels of constitutively active variant, the phospho-SHP2-Y542, of PTPN11/SHP2 and larger tumor size and lymph node positivity. We experimentally examined possible negative regulation of growth by PTPN11/SHP2 using MCF10A, a normal breast epithelial cell line. Knock-down of PTPN11/SHP2 resulted in increased cell migration, cell shape changes to mesenchymal morphology, and increased survival in cells treated with epirubicin, a DNA-damaging drug. However, it did not alter the rate of cell proliferation. It is possible that PTPN11/SHP2 might function as a tumor suppressor by potentiating proliferating cells with increased cell migration and resistance to apoptosis.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.30.228759v1?rss=1

Authors: Jacquier, V., Gitenay, D., Fritsch, S., Linares, L. K., Bonnet, S., Jalaguier, S., Cavaillès, V., Teyssier, C.

Abstract:

Cancer cells with uncontrolled proliferation preferentially depend on glycolysis to grow, even in the presence of oxygen. Cancer cell proliferation is sustained by the production of glycolytic intermediates, which are diverted into the pentose phosphate pathway. The transcriptional co-regulator RIP140 represses the activity of transcription factors that drive cell proliferation and metabolism, especially glycolysis. However, it is still unknown whether RIP140 is involved in cancer-associated glycolysis deregulation, and whether this involvement could impact tumor cell proliferation. Here we use cell proliferation and metabolic assays to demonstrate that RIP140-deficiency causes a glycolysis-dependent increase in breast tumor growth. RIP140 inhibits the expression of the glucose transporter GLUT3 and of the Glucose-6-Phosphate Dehydrogenase G6PD, the first enzyme of the pentose phosphate pathway. RIP140 thus impacts both this pathway and glycolysis to block cell proliferation. We further demonstrate that RIP140 and p53 jointly inhibit the transcription of the GLUT3 promoter, induced by the hypoxia inducible factor HIF-2&. Overall, our data establish RIP140 as a critical modulator of the p53/HIF cross-talk that controls cancer glycolysis.

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