- by Saucier, D., Jiang, X., Rajendran, D., Ravishankar, R., Butler, E., Marchetto, A., Kurmasheva, R., Gruenewald, T., Amatruda, J., Danuser, G.Organotropism results from the functional versatility of metastatic cancer cells to survive and proliferate in diverse microenvironments. This adaptivity can originate in clonal variation of the spreading tumor and is often empowered by epigenetic and molecular reprogramming of cell regulatory circuits. Related to organotropic colonization of metastatic sites are environmentally-sensitive, differential responses of cancer cells to therapeutic attack. Accordingly, understanding the organotropic profile of a cancer and probing the underlying driver mechanisms are of high clinical importance. However, determining systematically […]
- by PAI, P., Van Berckelaer, C., Van Laere, S., Bennion, A., Charity, T., Yang, J., Bertucci, F., Van Dam, P., Palmer, G. M., McCall, S., Dirix, L. Y., Ueno, N. T., Devi, G.Purpose: Inflammatory breast cancer (IBC) tumors are characterized by diffuse, clusters of cells found in dermal tissue and lymphatic vessels, known as tumor emboli. This study investigates the interaction between tumor emboli and the tumor immune microenvironment (TiME) that can foster survival signaling. Experimental Design: Spatial immunophenotyping was performed on clinical IBC samples. Ex vivo tumor emboli were generated from patient-derived cell lines cultured in a lymphatic-like platform and subjected to transcriptomic and proteomic analysis. A transgenic CX3cr1GFP murine model […]
- by Bernard, M., Ruiz, A., Diaz, J., Nunley, N., Dove, R., Heering, K., Bopardikar, S., Gallardo, A., Hashimoto, T., Agrawal, R., Smith, C., Wilde, B., Matulionis, N., Richards, H., Sharifi, M., Lang, J., Zhao, S., Haffner, M., Boutros, P. C., Christofk, H., Goldstein, A. S.Cells regularly adapt their metabolism in response to changes in their microenvironment or biosynthetic needs. Prostate cancer cells leverage this metabolic plasticity to evade therapies targeting the androgen receptor (AR) signaling pathway. For example, nucleotide metabolism plays a critical role in treatment-resistant prostate cancer by supporting DNA replication, DNA damage response and cell fate decisions. Identifying novel regulators of nucleotide metabolism in treatment-resistant cancer that are dispensable for the health of normal cells may lead to new therapeutic approaches less […]
- by Bhandarkar, A. A., Kelly-Foleni, N. E., Sarkar, D., Jeffs, A., Slatter, T., Braithwaite, A., Mehta, S.TP53 undergoes alternative splicing to produce multiple mRNA transcripts and protein isoforms, yet the effects of splice site mutations on isoform regulation, tumor biology, and clinical outcome remain unclear. Analysis of 23017 TP53 variants, including 18562 somatic mutations (pan-cancer datasets, cBioPortal) and 4455 germline variants (IARC database), identified recurrent donor (X32, X125, X224, X261, X331) and acceptor (X33, X126, X187, X225, X307, X332) splice site mutations. Germline variants showed nucleotide-specific transition biases. Most splice site mutations were associated with reduced […]
- by Kawabe, M., Yang, S., Bolanos, L. G., Takamatsu, S., Flores, S. A., Castro, P. D., Tsai, T.-Y., Kaga, A. N., Frederick, M. J., Sandulache, V., Kadara, H., Myers, J. N., Osman, A. A.Purpose: Cisplatin is the gold standard systemic agent for definitive treatment of HNSCC. The purpose of this study was to investigate the role of SPP1 in the progression and metastasis of cisplatin-resistant HNSCC, particularly in the context of NRF2 hyperactivation. Experimental Design: CDDP resistant HNSCC cell lines stably expressing various shRNA SPP1 constructs were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of silenced SPP1 in vitro and in vivo on […]
- by Mollaheydar, E., Saboury, B., Rahmim, A., Cytrynbaum, E. N.Purpose: Radiopharmaceutical therapies (RPTs) are showing significant value in targeting various forms of cancer; meanwhile, as an emerging paradigm there is significant room for optimization of RPTs. We developed a computational model towards improving therapeutic strategies via modification of dosage and timing of RPT injections. Methods: Our model simulates tumor growth, the pharmacokinetics of RPTs, and the radiobiological impact of radionuclide decay through energy deposition on tumor tissue. Specifically, we use the Hybrid Automata Library (HAL) to simulate tissue con- […]
- by Lam, C., Dhir, A., Jogdeo, C. M., Panda, S., Kapoor, E., Tang, S., Rivero, V., McIntyre, E. M., Xiao, P., Black, A. R., Hewitt, K., Swenson, S. A., Romanova, S., Oupicky, D., Hyde, R. K.PAMD-Ch17 is a polymer composed of the CXCR4 inhibitor AMD3100/Plerixafor with a cholesterol modification. In previous work, we showed that PAMD-Ch17, but not AMD3100, induces cell death and differentiation in mouse Acute Myeloid Leukemia cells. To investigate the mechanism of PAMD-Ch17 novel anti-leukemic effects, we tested PAMD-Ch17 against a panel of human leukemia cell lines and found that PAMD-Ch17 is effective against a variety of acute leukemias, with T-ALL cell lines being highly sensitive. Surprisingly, CXCR4 knock out T-ALL cells […]
- by Grimont, A., Falvo, D. J., Sisso, W. J., Zumbo, P., Chan, C. W., Santos, F., Pan, G., Cleveland, M., Yaron, T., Osterhoudt, A. S., Meng, Y., Zafra, M. P., Fall, W. B., Rendeiro, A. F., Hissong, E., Yantiss, R. K., Betel, D., Magnuson, M. A., Leach, S. D., Rustgi, A. K., Dow, L. E., Chandwani, R.Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic cancer (PDAC). How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRASG12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRASG12R/V […]
- by Anttila, J. M., Savelius, M., Somani, J., Nicorici, D., Munne, P. M., Id, L., Peura, A., Hiltunen, A. O., Aung, J., Awadhpersad, R., Prajapati, B., Peltonen, M., Ala-Hongisto, H., Gautam, P., Valimaki, M. J., Tervonen, T. A., Sapovalovaite, K., Devarajan, R., Perez, M. V. R., Mutka, M., Kovanen, P., Niinikoski, L., Meretoja, T., Mattson, J., Heikkila, P., Wennerberg, K., Arsenian-Henriksson, M., Westermarck, J., Aittokallio, T., Goga, A., Jackson, C. B., Nieminen, A. I., Klefstrom, J.In many cancers, stably elevated MYC levels drive persistent and concerted activation of cell growth promoting anabolic programs and the cell cycle in ways that are distinct from normal cells. Therefore, synthetic-lethal strategies to target MYC reprograming of these pathways may identify new selective anticancer therapies for the treatment of MYChigh tumors. Here, we identify enhanced mitochondrial respiration as a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD+ through complex I-mediated oxidation of […]
- by Maity, S., Alrubayan, M., Pradhan, P.We explored the fractal and multifractal characteristics of breast mammogram micrographs to identify quantitative biomarkers associated with breast cancer progression. In addition to conventional fractal and multifractal analyses, we employed a recently developed fractal-functional distribution method, which transforms fractal measures into Gaussian distributions for more robust statistical interpretation. Given the sparsity of mammogram intensity data, we also analyzed how variations in intensity thresholds, used for binary transformations of the fractal dimension, follow unique trajectories that may serve as novel indicators […]
- by Lefebvre, T. L., Oraiopoulou, M.-E., Bunce, E. V., Else, T. R., Wright, L. C., Golinska, M. A., Hacker, L., Brodie, C., Kupczak, S., Cheng, Y., Young, L., Sweeney, P. W., Bohndiek, S. E.There is a critical unmet clinical need to identify biomarkers that predict and detect radiotherapy response in cancer. Using the unique capabilities of multi-scale photoacoustic imaging (PAI) for depicting tumour oxygenation and vasculature in vivo, we identified surrogate biomarkers of radiation response in two human breast cancer models (MCF7 and MDA-MB-231), comparing hypofractionated delivery with an ablative single dose scheme. Ex vivo immunohistochemistry results underpinned findings from mesoscopic and multispectral tomographic PAI, performed 24h pre-RT, 24h post-RT, and at endpoint. […]
- by Ohlstrom, D., Pilcher, W. C., Michaud, M. E., Acharya, C. R., Satpathy, S., Gonzalez-Kozlova, E., Jayasinghe, R. G., Ferguson, K. E., Mumme, H., Nanda, S., Song, Y., Mantrala, S. K., Karagkouni, D., Schulman, J., Pabustan, N., Vieira Dos Santos, J., Sherbenou, D., Keats, J., Gout, A., Foltz, S., Lagana, A., Kourelis, T., Vij, R., Dhodapkar, M. V., Avigan, D., Cho, H. J., Baughn, L. B., Nooka, A., Lonial, S., Kumar, S., Samur, M., Vlachos, I., Ding, L., Gnjatic, S., Mulligan, G., Bhasin, M.Multiple myeloma (MM) is an incurable malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment. To investigate immune factors driving treatment response and resistance, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. Longitudinal analyses revealed that interferon gamma signaling impairs T cell memory after autologous stem cell transplant, while naive B cell abundance and […]
- by Sanawar, R., Guo, W.Basal-like breast cancer (BLBC) consists of the majority of triple-negative breast cancer subtype that has a higher degree of cellular plasticity owing to a greater number of stem-like cancer cells compared to other subtypes 1. BLBCs are thought to originate from the luminal progenitor cells despite their prominent basal-cell features. SOX9 is a key transcription factor which is expressed selectively in estrogen receptor-negative luminal progenitors in postnatal mammary glands. During BLBC progression, SOX9 upregulation is required for the de-differentiation of […]
- by Postlmayr, A., Sanchez Bergman, A., Torrejon Diaz, J., Ciraulo, B., Yan, S., Hofmann, N., Carbajal, S., Dobler, R., Machaalani, C., Priego-Gonzalez, L., De Micheli, A. J., Berenjeno-Correa, E., Baroncini, L., Grotzer, M. A., Tabori, U., Hawkins, C., Ayrault, O., Zuckermann, M., Baumgartner, M., Guerreiro Stuecklin, A. S.ALK and ROS1 fusions are emerging as key drivers of infant-type hemispheric gliomas (IHG). With diverse gene partners, the impact of ALK and ROS1 oncoprotein heterogeneity on glioma biology remains unknown. We developed an integrative phospho-proteomic and transcriptomic approach to discover biological functions regulated by five IHG-associated fusions: CCDC88A::ALK, PPP1CB::ALK, GOPC::ROS1, CLIP1::ROS1 and KIF21A::ROS1. Here, we report fusion-specific oncogenic functions conferred by the 5' gene partner, including increased cell motility driven by microtubule-interacting fusions CCDC88A::ALK and CLIP1::ROS1. All studied fusions […]
- by Tirado, C. A. R., Riaz, T. A., Rodrigues, A. A., Kale, N., Satheeshkumar, S. J., Perez-Gallegos, A., Olmeda, D., Soengas, M. S., Sosa, M. S.A significant factor in cancer-related mortality in melanoma is the appearance of intrinsically aggressive distal metastases. This recurrence frequently results from the awakening of dormant disseminated cancer cells (DCCs). One of the most puzzling clinical features in this disease is that DCCs rapidly develop into metastases in certain melanoma patients, while remaining inactive in others. We have previously identified NR2F1 as a driver of dormancy, but the mechanisms underlying its regulation, particularly when DCC are ''awakened'', are poorly understood. This […]
- by Hovey, O. F., Frederick, M. I., Quach, Q. M., Kakadia, J. H., Wu, A., Yang, K., Wu, T., Ruan, X., Kaneko, T., Voss, C., Heinemann, I. U., Li, S. S.Resistance of chronic myeloid leukemia (CML) to BCR-ABL tyrosine kinase inhibitors (TKIs) can arise from kinase-activating mutations within the ABL kinase domain, BCR-ABL gene amplification, or mechanisms independent of BCR-ABL. Through quantitative mass spectrometry analysis of K562, a commonly used CML cell line, and ImR, an imatinib-resistant derivative we developed, global changes in the proteome and phosphoproteome were identified. LIN28A, a multi-functional RNA-binding protein, emerged as a central player in driving imatinib resistance. Several key observations underscore the critical role […]
- by Li, H., Melnyk, J. E., Fu, B. X. H., Shrestha, R., Zhang, M., Sjostrom, M., Feng, S., Anderson, J., Han, W., Chesner, L. N., Shin, H. J., Farsh, T., Suarez, H. J., Nath, S., Chou, J., Das, R., Egusa, E. A., Calvert, M., Kishishita, A., Barpanda, A., Zhu, J., Maheshwari, A., Chen, W. S., Alshalalfa, M., Winters, A., Hua, J. T., Liu, T., Davicioni, E., Wiita, A. P., Stohr, B. A., Siddiqui, J., Huang, B., Small, E. J., Shokat, K. M., Nelson, P., Quigley, D. A., Wasmuth, E. V., Gilbert, L. A., Feng, F. Y.The androgen receptor (AR) is a critical driver of prostate cancer (PCa). To study regulators of AR protein levels and oncogenic activity, we created the first live cell quantitative endogenous AR fluorescent reporters. Leveraging this novel AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators including HOXB13 and GATA2 and also unexpected top hits including PTGES3, a poorly characterized gene in PCa. […]
- by Wang, X., Duong, L., Qin, Y., Parrotta, R., Purohit, P. K., Fang, Y., Liu, G., He, J., Wen, J., Liu, Y., Zhang, Y., Zhao, J., Schafer, Z. T., Lu, X., Szegezdi, E., Lu, X.Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of von Hippel-Lindau (VHL) and the consequent activation of hypoxia-inducible factor- (HIF, especially HIF2) plays an essential role in ccRCC initiation and progression. The approved HIF2 inhibitor belzutifan faces the challenge of resistance, presenting an opportunity of co-targeting HIF2 and another vulnerability. This study elucidates the synthetic essentiality of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in VHL-deficient ccRCC, uncovering a novel reciprocal regulation […]
- by Zhou, Y., Kim, J. T., Kwon, J. W., Lee, G. Y., Son, H. M., Lee, K. H., Qiu, S., Lee, H. J.Garcinone C, a xanthone derived from Garcinia mangostana L, possesses antioxidant and anti-cancer effects. However, its role in gastric cancer remains unexplored. This study aimed to investigate the effects of garcinone C on gastric cancer cell proliferation and its underlying mechanism. We found that garcinone C suppressed gastric cancer cell growth by inducing G0/G1 arrest and apoptosis in a dose-dependent manner. Furthermore, garcinone C downregulated G0/G1 phase markers Cyclin D1 and p21, as well as apoptosis markers Bax, Bcl-2, cleaved-PARP, […]
- by Calleja, v., Henry, J. C., Cobbaut, M., Sewell, J., Rizzoti, K., Houghton, F., Boeing, S., Anyanwu, N., Varsani-Brown, S., Snoeks, T., Suarez-Bonnet, A., Priestnall, S. L., McDonald, N. Q., Cameron, A. J., Parker, P. J.The penetrant PRKCA D463H mutation, a biomarker and potential driver in chordoid glioma, was found to provoke the development of chondrosarcomas in heterozygous knock-in mice. This mutation entirely abrogates kinase activity, but strikingly no oncogenic phenotype is observed for the related inactivating mutation D463N indicating that the lack of activity is not the driver. In cells, the D463H mutant closely mirrored PKC WT behaviours and retained ATP binding, contrary to the related D463N mutant. Mechanistically, the PKC D463H mutant protein […]
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