bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–08–01
nineteen papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-κB/bone remodeling factors signaling.
  2. Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation.
  3. ClonMapper Isolates and Characterizes Clones Causing Treatment Resistance.
  4. Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors.
  5. Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS mutant lung cancer.
  6. MASTL regulates EGFR signaling to impact pancreatic cancer progression.
  7. An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer.
  8. Overcoming PD-1 Blockade Resistance With CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients With Metastatic Melanoma.
  9. Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma.
  10. Blocking short-form Ron eliminates breast cancer metastases through accumulation of stem-like CD4+ T cells that subvert immunosuppression.
  11. SMAD4 represses FOSL1 expression and pancreatic cancer metastatic colonization.
  12. Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma.
  13. Modeling metastasis in mice: a closer look.
  14. Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.
  15. UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth.
  16. Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis.
  17. The immunological and metabolic landscape in primary and metastatic liver cancer.
  18. In silico saturation mutagenesis of cancer genes.
  19. A pan-cancer organoid platform for precision medicine.
  1. Mol Cancer. 2021 Jul 29. 20(1): 98
    Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-κB/bone remodeling factors signaling.
    Yingru Xu, Shuxia Zhang, Xinyi Liao, Man Li, Suwen Chen, Xincheng Li, Xingui Wu, Meisongzhu Yang, Miaoling Tang, Yameng Hu, Ziwen Li, Ruyuan Yu, Mudan Huang, Libing Song, Jun Li.
       BACKGROUND: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown.
    METHODS: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays.
    RESULTS: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively.
    CONCLUSION: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.
    Keywords:  Bone metastasis; Bone remodeling factor; Breast cancer; NF-κB; circIKBKB
    DOI:  https://doi.org/10.1186/s12943-021-01394-8
  2. Oncogene. 2021 Jul 30.
    Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation.
    Shaoyang Zhang, Xueming Guo, Xiufeng Liu, Zhixiong Zhong, Shulan Yang, Haihe Wang.
      Metastatic recurrence is still a major challenge in breast cancer treatment, but the underlying mechanisms remain unclear. Here, we report that a small adaptor protein, SH3BGRL, is upregulated in the majority of breast cancer patients, especially elevated in those with metastatic relapse, indicating it as a marker for the poor prognosis of breast cancer. Physiologically, SH3BGRL can multifunctionally promote breast cancer cell tumorigenicity, migration, invasiveness, and efficient lung colonization in nude mice. Mechanistically, SH3BGRL downregulates the acting-binding protein profilin 1 (PFN1) by accelerating the translation of the PFN1 E3 ligase, STUB1 via SH3BGRL interaction with ribosomal proteins, or/and enhancing the interaction of PFN1 with STUB1 to accelerate PFN1 degradation. Loss of PFN1 consequently contributes to downstream multiple activations of AKT, NF-kB, and WNT signaling pathways. In contrast, the forced expression of compensatory PFN1 in SH3BGRL-high cells efficiently neutralizes SH3BGRL-induced metastasis and tumorigenesis with PTEN upregulation and PI3K-AKT signaling inactivation. Clinical analysis validates that SH3BGRL expression is negatively correlated with PFN1 and PTEN levels, but positively to the activations of AKT, NF-kB, and WNT signaling pathways in breast patient tissues. Our results thus suggest that SH3BGRL is a valuable prognostic factor and a potential therapeutic target for preventing breast cancer progression and metastasis.
    DOI:  https://doi.org/10.1038/s41388-021-01970-8
  3. Cancer Discov. 2021 Jul 30.
    ClonMapper Isolates and Characterizes Clones Causing Treatment Resistance.
      Leukemia cell clones that rebound after treatment have differential levels of therapeutic tolerance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-106
  4. Oncogene. 2021 Jul 29.
    Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors.
    Kristina M Whately, Maria A Voronkova, Abha Maskey, Jasleen Gandhi, Juergen Loskutov, Hyeran Choi, Sila Yanardag, Dongquan Chen, Sijin Wen, Naira V Margaryan, Matthew B Smolkin, Marc L Purazo, Gangqing Hu, Elena N Pugacheva.
      Metastatic breast cancer causes most breast cancer-associated deaths, especially in triple negative breast cancers (TNBC). The metastatic drivers of TNBCs are still poorly understood, and effective treatment non-existent. Here we reveal that the presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia-Inducible Factor-1) signaling. Nuclear AURKA activates transcription of "hypoxia-induced genes" under normoxic conditions (pseudohypoxia) and without upregulation of oxygen-sensitive HIF1A subunit. We uncover that AURKA preferentially binds to HIF1B and co-localizes with the HIF complex on DNA. The mass-spectrometry analysis of the AURKA complex further confirmed the presence of CBP and p300 along with other TFIIB/RNApol II components. Importantly, the expression of multiple HIF-dependent genes induced by nuclear AURKA (N-AURKA), including migration/invasion, survival/death, and stemness, promote early cancer dissemination. These results indicate that nuclear, but not cytoplasmic, AURKA is a novel driver of early metastasis. Analysis of clinical tumor specimens revealed a correlation between N-AURKA presence and decreased patient survival. Our results establish a mechanistic link between two critical pathways in cancer metastasis, identifying nuclear AURKA as a crucial upstream regulator of the HIF1 transcription complex and a target for anti-metastatic therapy.
    DOI:  https://doi.org/10.1038/s41388-021-01969-1
  5. JCI Insight. 2021 Jul 22. pii: 148392. [Epub ahead of print]
    Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS mutant lung cancer.
    Aparna Padhye, Jessica M Konen, B Leticia Rodriguez, Jared J Fradette, Joshua K Ochieng, Lixia Diao, Jing Wang, Wei Lu, Luisa S Solis, Harsh Batra, Maria G Raso, Michael D Peoples, Rosalba Minelli, Alessandro Carugo, Christopher A Bristow, Don L Gibbons.
      Lack of sustained response to therapeutic agents in patients with KRAS mutant lung cancer poses a major challenge and arises partly due to intratumor heterogeneity that defines phenotypically distinct tumor subpopulations. To attain better therapeutic outcomes it is important to understand the differential therapeutic sensitivities of tumor cell subsets. Epithelial-to-mesenchymal transition (EMT) is a biologic phenomenon that can alter the state of cells along a phenotypic spectrum and cause transcriptional rewiring to produce distinct tumor cell subpopulations. We utilized functional shRNA screens, in vitro and in vivo models to identify and confirm an increased dependence of mesenchymal tumor cells on CDK4 for survival, as well as a mechanism of resistance to MEK inhibitors. High ZEB1 levels in mesenchymal tumor cells repressed p21, leading to perturbed CDK4 pathway activity. Increased dependence on CDK4 rendered mesenchymal cancer cells particularly vulnerable to selective CDK4 inhibitors. Co-administration of CDK4 and MEK inhibitors in heterogeneous tumors effectively targeted different tumor subpopulations, subverting the resistance to either single agent treatment.
    Keywords:  Lung cancer; Oncology; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.148392
  6. Oncogene. 2021 Jul 30.
    MASTL regulates EGFR signaling to impact pancreatic cancer progression.
    Iram Fatima, Susmita Barman, JayaPrakash Uppada, Shailender Chauhan, Sanchita Rauth, Satyanarayana Rachagani, Moorthy Palanimuthu Ponnusamy, Lynette Smith, Geoffrey Talmon, Amar B Singh, Surinder K Batra, Punita Dhawan.
      Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (microtubule-associated serine/threonine-protein kinase-like (MASTL)) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role in PC remains unknown. Based on a comprehensive investigation involving PC patient samples, murine models of PC progression (Kras;PdxCre-KC and Kras;p53;PdxCre-KPC), and loss and gain of function studies, we report a previously undescribed critical role of MASTL in promoting cancer malignancy and therapy resistance. Mechanistically, MASTL promotes PC by modulating the epidermal growth factor receptor protein stability and, thereupon, kinase signaling. We further demonstrate that combinatorial therapy targeting MASTL promotes the efficacy of the cell-killing effects of Gemcitabine using both genetic and pharmacological inhibitions. Taken together, this study identifies a key role of MASTL in promoting PC progression and its utility as a novel target in promoting sensitivity to the anti-PC therapies.
    DOI:  https://doi.org/10.1038/s41388-021-01951-x
  7. Nat Commun. 2021 07 29. 12(1): 4601
    An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer.
    Rajdeep Das, Martin Sjöström, Raunak Shrestha, Christopher Yogodzinski, Emily A Egusa, Lisa N Chesner, William S Chen, Jonathan Chou, Donna K Dang, Jason T Swinderman, Alex Ge, Junjie T Hua, Shaheen Kabir, David A Quigley, Eric J Small, Alan Ashworth, Felix Y Feng, Luke A Gilbert.
      Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.
    DOI:  https://doi.org/10.1038/s41467-021-24919-7
  8. Cancer Discov. 2021 Jul 29. pii: candisc.0425.2021. [Epub ahead of print]
    Overcoming PD-1 Blockade Resistance With CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients With Metastatic Melanoma.
    Antoni Ribas, Theresa Medina, John M Kirkwood, Yousef Zakharia, Rene Gonzalez, Diwakar Davar, Bartosz Chmielowski, Katie M Campbell, Riyue Bao, Heather Kelley, Aaron Morris, David Mauro, James E Wooldridge, Jason J Luke, George J Weiner, Arthur M Krieg, Mohammed M Milhem.
      Patients with advanced melanoma that is resistant to programmed death-1 (PD-1) blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong interferon response to induce and attract antitumor T cells. In the dose-escalation part of this phase 1b study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an interferon-γ gene signature following treatment, as well as increased systemic expression of the interferon-inducible chemokine CXCL10.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0425
  9. Oncogene. 2021 Jul 24.
    Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma.
    Beike Wang, Wei Zhang, Gao Zhang, Lawrence Kwong, Hezhe Lu, Jiufeng Tan, Norah Sadek, Min Xiao, Jie Zhang, Marilyne Labrie, Sergio Randell, Aurelie Beroard, Eric Sugarman, Vito W Rebecca, Zhi Wei, Yiling Lu, Gordon B Mills, Jeffrey Field, Jessie Villanueva, Xiaowei Xu, Meenhard Herlyn, Wei Guo.
      Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma.
    DOI:  https://doi.org/10.1038/s41388-021-01911-5
  10. Cancer Discov. 2021 Jul 30. pii: candisc.1172.2020. [Epub ahead of print]
    Blocking short-form Ron eliminates breast cancer metastases through accumulation of stem-like CD4+ T cells that subvert immunosuppression.
    Shu-Chin Alicia Lai, Harika Gundlapalli, H Atakan Ekiz, Amanda Jiang, Elvelyn Fernandez, Alana L Welm.
      Immunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micro-metastases, augmented tumor-specific T cell responses, and nearly eliminated breast cancer metastasis in mice. Lack of host SF-Ron caused stem-like TCF1+ CD4+ T cells with type I differentiation potential to accumulate in metastases and prevent metastatic outgrowth. There was a corresponding increase in tumor-specific CD8+ T cells, which were also required to eliminate lung metastases. Treatment of mice with a Ron kinase inhibitor increased tumor-specific CD8+ T cells and protected from metastatic outgrowth. These data provide strong pre-clinical rationale to pursue small molecule Ron kinase inhibitors for prevention and treatment of metastatic breast cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1172
  11. Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00860-3. [Epub ahead of print]36(4): 109443
    SMAD4 represses FOSL1 expression and pancreatic cancer metastatic colonization.
    Chao Dai, Jonathan P Rennhack, Taylor E Arnoff, Maneesha Thaker, Scott T Younger, John G Doench, August Yue Huang, Annan Yang, Andrew J Aguirre, Belinda Wang, Evan Mun, Joyce T O'Connell, Ying Huang, Katherine Labella, Jessica A Talamas, Ji Li, Nina Ilic, Justin Hwang, Andrew L Hong, Andrew O Giacomelli, Ole Gjoerup, David E Root, William C Hahn.
      Metastasis is a complex and poorly understood process. In pancreatic cancer, loss of the transforming growth factor (TGF)-β/BMP effector SMAD4 is correlated with changes in altered histopathological transitions, metastatic disease, and poor prognosis. In this study, we use isogenic cancer cell lines to identify SMAD4 regulated genes that contribute to the development of metastatic colonization. We perform an in vivo screen identifying FOSL1 as both a SMAD4 target and sufficient to drive colonization to the lung. The targeting of these genes early in treatment may provide a therapeutic benefit.
    Keywords:  FOSL1; PDAC; SMAD4; colonization; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2021.109443
  12. Cancer Res. 2021 Jul 28. pii: canres.0774.2021. [Epub ahead of print]
    Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma.
    Ksenija Nesic, Olga Kondrashova, Rachel M Hurley, Cordelia D McGehee, Cassandra J Vandenberg, Gwo-Yaw Ho, Elizabeth Lieschke, Genevieve Dall, Nirashaa Bound, Kristy Shield-Artin, Marc Radke, Ashan Musafer, Zi Qing Chai, Mohammad Reza Eftekhariyan Ghamsari, Maria I Harrell, Damien Kee, Inger Olesen, Orla McNally, Nadia Traficante, Australian Ovarian Cancer Study, Anna DeFazio, David D L Bowtell, Elizabeth M Swisher, S John Weroha, Katia Nones, Nicola Waddell, Scott H Kaufmann, Alexander Dobrovic, Matthew J Wakefield, Clare L Scott.
      In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved. In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages. In a cohort of 11 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic 'scarring', indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after 6 lines of therapy (4 platinum-based), whilst another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neo-adjuvant chemotherapy. As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0774
  13. Trends Cancer. 2021 Jul 21. pii: S2405-8033(21)00145-X. [Epub ahead of print]
    Modeling metastasis in mice: a closer look.
    Arianna Giacobbe, Cory Abate-Shen.
      Unraveling the multifaceted cellular and physiological processes associated with metastasis is best achieved by using in vivo models that recapitulate the requisite tumor cell-intrinsic and -extrinsic mechanisms at the organismal level. We discuss the current status of mouse models of metastasis. We consider how mouse models can refine our understanding of the underlying biological and molecular processes that promote metastasis, and we envisage how the application of new technologies will further enhance investigations of metastasis at single-cell resolution in the context of the whole organism. Our view is that investigations based on state-of-the-art mouse models can propel a holistic understanding of the biology of metastasis, which will ultimately lead to the discovery of new therapeutic opportunities.
    Keywords:  genetically engineered mouse models (GEMMs); metastasis; syngeneic models; xenograft models
    DOI:  https://doi.org/10.1016/j.trecan.2021.06.010
  14. Clin Cancer Res. 2021 Jul 28. pii: clincanres.1059.2021. [Epub ahead of print]
    Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.
    Kenneth C Anderson, Daniel Auclair, Stacey J Adam, Amit Agarwal, Melissa Anderson, Herve Avet-Loiseau, Mark Bustoros, Jessica Chapman, Dana E Connors, Ajeeta Dash, Alessandra Di Bacco, Ling Du, Thierry Facon, Juan Flores-Montero, Francesca Gay, Irene M Ghobrial, Nicole J Gormley, Ira Gupta, Howard Higley, Jens Hillengass, Bindu Kanapuru, Dickran Kazandjian, Gary J Kelloff, Ilan R Kirsch, Brandon E Kremer, Ola Landgren, Elizabeth D Lightbody, Oliver C Lomas, Sagar Lonial, Maria Victoria Mateos, Rocio Montes de Oca, Lata Mukundan, Nikhil C Munshi, Elizabeth K O'Donnell, Alberto Orfao, Bruno Paiva, Reshma Patel, Trevor J Pugh, Karthik Ramasamy, Jill Ray, Mikhail Roshal, Jeremy A Ross, Caroline C Sigman, Katie L Thoren, Suzanne Trudel, Gary A Ulaner, Nancy Valente, Brendan M Weiss, Elena Zamagni, Shaji K Kumar.
      The development of novel agents has transformed the treatment paradigm for multiple myeloma (MM), with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in MM patients. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory MM, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in MM is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1059
  15. Proc Natl Acad Sci U S A. 2021 Aug 03. pii: e2103592118. [Epub ahead of print]118(31):
    UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth.
    Andrew L Wolfe, Qingwen Zhou, Eneda Toska, Jacqueline Galeas, Angel A Ku, Richard P Koche, Sourav Bandyopadhyay, Maurizio Scaltriti, Carlito B Lebrilla, Frank McCormick, Sung Eun Kim.
      UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)-TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.
    Keywords:  N-glycosylation; PDAC; UDP-glucose; UGP2; glycogen
    DOI:  https://doi.org/10.1073/pnas.2103592118
  16. Elife. 2021 Jul 28. pii: e65418. [Epub ahead of print]10
    Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis.
    Xinbo Qiao, Yixiao Zhang, Lisha Sun, Qingtian Ma, Jie Yang, Liping Ai, Jinqi Xue, Guanglei Chen, Hao Zhang, Ce Ji, Xi Gu, Haixin Lei, Yongliang Yang, Caigang Liu.
      Tumor metastasis remains the main cause of breast cancer-related deaths, especially delayed breast cancer distant metastasis. The current study assessed the frequency of CD44-/CD24- breast cancer cells in 576 tissue specimens for associations with clinicopathological features and metastasis and investigated the underlying molecular mechanisms. The results indicated that higher frequency (≥19.5%) of CD44-/CD24- cells was associated with delayed postoperative breast cancer metastasis. Furthermore, CD44-/CD24- triple negative breast cancer (TNBC) cells spontaneously converted into CD44+/CD24- cancer stem cells (CSCs) with properties similar to CD44+/CD24- CSCs from primary human breast cancer cells and parental TNBC cells in terms of stemness marker expression, self-renewal, differentiation, tumorigenicity and lung metastasis in vitro and in NOD/SCID mice. RNA sequencing identified several differentially expressed genes (DEGs) in newly converted CSCs and RHBDL2, one of the DEGs, expression was up-regulated. More importantly, RHBDL2 silencing inhibited the YAP1/USP31/NF-κB signaling and attenuated spontaneous CD44-/CD24- cell conversion into CSCs and their mammosphere formation. These findings suggest that the frequency of CD44-/CD24- tumor cells and RHBDL2 may be valuable for prognosis of delayed breast cancer metastasis, particularly for TNBC.
    Keywords:  cancer biology; human; medicine; mouse
    DOI:  https://doi.org/10.7554/eLife.65418
  17. Nat Rev Cancer. 2021 Jul 29.
    The immunological and metabolic landscape in primary and metastatic liver cancer.
    Xin Li, Pierluigi Ramadori, Dominik Pfister, Marco Seehawer, Lars Zender, Mathias Heikenwalder.
      The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.
    DOI:  https://doi.org/10.1038/s41568-021-00383-9
  18. Nature. 2021 Jul 28.
    In silico saturation mutagenesis of cancer genes.
    Ferran Muiños, Francisco Martínez-Jiménez, Oriol Pich, Abel Gonzalez-Perez, Nuria Lopez-Bigas.
      Despite the existence of good catalogues of cancer genes1,2, identifying the specific mutations of those genes that drive tumorigenesis across tumour types is still a largely unsolved problem. As a result, most mutations identified in cancer genes across tumours are of unknown significance to tumorigenesis3. We propose that the mutations observed in thousands of tumours-natural experiments testing their oncogenic potential replicated across individuals and tissues-can be exploited to solve this problem. From these mutations, features that describe the mechanism of tumorigenesis of each cancer gene and tissue may be computed and used to build machine learning models that encapsulate these mechanisms. Here we demonstrate the feasibility of this solution by building and validating 185 gene-tissue-specific machine learning models that outperform experimental saturation mutagenesis in the identification of  driver and passenger mutations. The models and their assessment of each mutation are designed to be interpretable, thus avoiding a black-box prediction device. Using these models, we outline the blueprints of potential driver mutations in cancer genes, and demonstrate the role of mutation probability in shaping the landscape of observed driver mutations. These blueprints will support the interpretation of newly sequenced tumours in patients and the study of the mechanisms of tumorigenesis of cancer genes across tissues.
    DOI:  https://doi.org/10.1038/s41586-021-03771-1
  19. Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00846-9. [Epub ahead of print]36(4): 109429
    A pan-cancer organoid platform for precision medicine.
    Brian M Larsen, Madhavi Kannan, Lee F Langer, Benjamin D Leibowitz, Aicha Bentaieb, Andrea Cancino, Igor Dolgalev, Bridgette E Drummond, Jonathan R Dry, Chi-Sing Ho, Gaurav Khullar, Benjamin A Krantz, Brandon Mapes, Kelly E McKinnon, Jessica Metti, Jason F Perera, Tim A Rand, Veronica Sanchez-Freire, Jenna M Shaxted, Michelle M Stein, Michael A Streit, Yi-Hung Carol Tan, Yilin Zhang, Ende Zhao, Jagadish Venkataraman, Martin C Stumpe, Jeffrey A Borgia, Ashiq Masood, Daniel V T Catenacci, Jeremy V Mathews, Demirkan B Gursel, Jian-Jun Wei, Theodore H Welling, Diane M Simeone, Kevin P White, Aly A Khan, Catherine Igartua, Ameen A Salahudeen.
      Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.
    DOI:  https://doi.org/10.1016/j.celrep.2021.109429
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