bims-tucedo 2020-04-19 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2020–04–19
38 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

Molecular principles of metastasis: a hallmark of cancer revisited.
Janus Face of Drug-Induced Tetraploidy in Non-Hodgkin Lymphoma.
Nuclear translocation of PLSCR1 activates STAT1 signaling in basal-like breast cancer.
Disseminated Tumor Cells and Dormancy in Breast Cancer Progression.
The force awakens: metastatic dormant cancer cells.
Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.
Tumor cell-derived Angiopoietin-2 promotes metastasis in melanoma.
Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets.
SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression.
Acquired Resistance to Immune Checkpoint Inhibitors.
Genome-wide single-nucleotide resolution of oxaliplatin-DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines.
Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition.
The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution.
Advancing Cancer Research and Medicine with Single-Cell Genomics.
Overcoming Endocrine Resistance in Breast Cancer.
SHP-2 and PD-L1 inhibition combined with radiotherapy enhances systemic antitumor effects in an anti-PD-1-resistant model of non-small-cell lung cancer.
Targeting TGFβ Signalling in Cancer: Toward Context-Specific Strategies.
RNA-seq reveals novel CircRNAs involved in breast cancer progression and patient therapy response.
Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance.
A20 and RBX1 regulate brentuximab vedotin sensitivity in Hodgkin Lymphoma models.
Guidelines and definitions for research on epithelial-mesenchymal transition.
Liquid Biopsy-Based Biomarkers of Treatment Response and Resistance.
PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression.
SLFN11 inhibits hepatocellular carcinoma tumorigenesis and metastasis by targeting RPS4X via mTOR pathway.
Drug-Induced Senescence Exposes Pancreatic Cancer Vulnerabilities.
Immunotherapy Is Active in MMR-Deficient and MMR-Proficient Colon Cancer.
Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy.
The phosphorylation of CD147 by Fyn plays a critical role for melanoma cells growth and metastasis.
Response and Resistance to BCR-ABL1-Targeted Therapies.
Pathological tumor response following immune checkpoint blockade for deficient mismatch repair advanced colorectal cancer.
Targeting p63 upregulation abrogates resistance to MAPK inhibitors in melanoma.
circPRRC2A promotes angiogenesis and metastasis through epithelial-mesenchymal transition and upregulates TRPM3 in renal cell carcinoma.
CAR T-cell therapy for relapsed or refractory mantle-cell lymphoma.
Preclinical validation of a novel metastasis-inhibiting Tie1 function-blocking antibody.
Phase II Study of Ensituximab, a Novel Chimeric Monoclonal Antibody, in Adults with Unresectable, Metastatic Colorectal Cancer.
Toward a More Precise Future for Oncology.
Patient-derived organoids from multiple colorectal cancer liver metastases reveal moderate intra-patient pharmacotranscriptomic heterogeneity.
The Complex Interplay between Antioxidants and ROS in Cancer.

Signal Transduct Target Ther. 2020 Mar 12. 5(1): 28

Molecular principles of metastasis: a hallmark of cancer revisited.

Jawad Fares, Mohamad Y Fares, Hussein H Khachfe, Hamza A Salhab, Youssef Fares.

Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

DOI: https://doi.org/10.1038/s41392-020-0134-x
Trends Cancer. 2020 Apr 11. pii: S2405-8033(20)30118-7. [Epub ahead of print]

Janus Face of Drug-Induced Tetraploidy in Non-Hodgkin Lymphoma.

Daruka Mahadevan, Gregory C Rogers.

  Anticancer agents often cause drug-induced tetraploidy (DIT) in cancer cells. DIT is not only a mechanism of inherited drug resistance, but proliferating DIT cells can produce progeny with increased ploidy or aneuploid genomes that drive aggressive disease. Here, we explore combinatorial therapeutic strategies for either preventing or eliminating DIT cells.

Keywords:  aneuploidy; drug resistance; polyploidy; tetraploidy; tumor evolution

DOI:  https://doi.org/10.1016/j.trecan.2020.03.009
Theranostics. 2020 ;10(10): 4644-4658

Nuclear translocation of PLSCR1 activates STAT1 signaling in basal-like breast cancer.

Panpan Huang, Ruocen Liao, Xingyu Chen, Xuebiao Wu, Xiaoli Li, Yifan Wang, Qianhua Cao, Chenfang Dong.

  Rationale: Basal-like breast cancer (BLBC) is associated with high grade, distant metastasis, and poor prognosis; however, the mechanism underlying aggressiveness of BLBC is still unclear. Emerging evidence has suggested that phospholipid scramblase 1 (PLSCR1) is involved in tumor progression. Here, we aimed to study the possible involvement and molecular mechanisms of PLSCR1 contributing to the aggressive behavior of BLBC. Methods: The potential functions of PLSCR1 in breast cancer cells were assessed by Western blotting, colony formation, migration and invasion, Cell Counting Kit-8 assay, mammosphere formation and flow cytometry. The relationship between nuclear translocation of PLSCR1 and transactivation of STAT1 was examined by immunostaining, co-IP, ChIP, and quantitative reverse transcription PCR. The effect of PLSCR1 expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model. Results: Compared to other subtypes, PLSCR1 was considerably increased in BLBC. Phosphorylation of PLSCR1 at Tyr 69/74 contributed to the nuclear translocation of this protein. PLSCR1 was enriched in the promoter region of STAT1 and enhanced STAT3 binding to the STAT1 promoter, resulting in transactivation of STAT1; STAT1 then enhanced cancer stem cell (CSC)-like properties that promoted BLBC progression. The knockdown of PLSCR1 led to significant inhibitory effects on proliferation, migration, invasion, tumor growth and lung metastasis of BLBC cells. Clinically, high PLSCR1 expression was strongly correlated with large tumor size, high grade, metastasis, chemotherapy resistance, and poor survival, indicating poor prognosis in breast cancer patients. Conclusions: Our data show that overexpression and nuclear translocation of PLSCR1 provide tumorigenic and metastatic advantages by activating STAT1 signaling in BLBC. This study not only reveals a critical mechanism of how PLSCR1 contributes to BLBC progression, but also suggests potential prognostic indicators and therapeutic targets for this challenging disease.

Keywords:  PLSCR1; STAT1 signaling; STAT3; basal-like breast cancer; cancer stem cells

DOI:  https://doi.org/10.7150/thno.43150
Adv Exp Med Biol. 2020 ;1220 35-43

Disseminated Tumor Cells and Dormancy in Breast Cancer Progression.

Malgorzata Banys-Paluchowski, Florian Reinhardt, Tanja Fehm.

  Hematogenous dissemination of single cancer cells is a common phenomenon in patients with solid tumors. These cells may experience different fates: most will die during the process; some will grow into metastasis and some will persist in secondary homing sites for many years in a state referred to as dormancy. The mechanisms of this state are still not clear; single cancer cells can survive either by completely withdrawing from the cell cycle or by continuing to proliferate at a slow rate that is counterbalanced by cell death. Another hypothesis assumes that at least some of dormant tumor cells feature stem cell-like characteristics that may contribute to their extremely long half-lives and enhance chemotherapy resistance. Breast cancer is particularly known for prolonged periods of clinical freedom of disease (sometimes up to 20-30 years), followed by a distant relapse. In this chapter, we explore the relationship between the clinical phenomenon of tumor dormancy and the disseminated tumor cells and discuss the potential implications for treatment.

Keywords:  Angiogenesis; Breast cancer; Cancer dormancy; Circulating tumor cells (CTCs); Disseminated tumor cells (DTCs); Metastasis; Microenvironment

DOI:  https://doi.org/10.1007/978-3-030-35805-1_3
Exp Mol Med. 2020 Apr 16.

The force awakens: metastatic dormant cancer cells.

So-Yeon Park, Jeong-Seok Nam.

Recurrent cancer that spreads to distant sites is the leading cause of disease-related death among cancer patients. Cancer cells are likely to disseminate during cancer progression, and some may enter dormancy, remaining viable but not increasing. These dormant cancer cells (DCCs) are rarely detectable with current diagnostic systems. Moreover, they can interpret homoeostatic signals from the microenvironment, thereby evading immune surveillance and chemotherapy. Eventually, DCCs can reawaken in response to signals, which are not yet fully understood, resulting in recurrence and metastasis. Therefore, understanding the biology of DCC reawakening is key to preventing metastasis. Over the last decade, a growing body of literature has revealed the mechanisms involved in cancer dormancy and reawakening. The cytotoxic activity of immune cells can cause cancer cells to enter a dormant state, and chronic inflammation can reactivate cancer proliferation at distant sites. Upon the binding of circulating DCCs to extracellular molecules, various signaling cascades are activated and reinitiate cell proliferation. In the present review, we attempt to consolidate the existing literature to provide a framework for the understanding of this crucial step in cancer progression.

DOI: https://doi.org/10.1038/s12276-020-0423-z
Nat Cell Biol. 2020 Apr 13.

Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.

Snahlata Singh, Sushil Kumar, Ratnesh Kumar Srivastava, Ajeya Nandi, Gatha Thacker, Hemma Murali, Sabrina Kim, Mary Baldeon, John Tobias, Mario Andres Blanco, Rizwan Saffie, M Raza Zaidi, Satrajit Sinha, Luca Busino, Serge Y Fuchs, Rumela Chakrabarti.

Triple-negative breast cancer (TNBC) is characterized by a high degree of immune infiltrate in the tumour microenvironment, which may influence the fate of TNBC cells. We reveal that loss of the tumour suppressive transcription factor Elf5 in TNBC cells activates intrinsic interferon-γ (IFN-γ) signalling, promoting tumour progression and metastasis. Mechanistically, we find that loss of the Elf5-regulated ubiquitin ligase FBXW7 ensures stabilization of its putative protein substrate IFN-γ receptor 1 (IFNGR1) at the protein level in TNBC. Elf5low tumours show enhanced IFN-γ signalling accompanied by an increase of immunosuppressive neutrophils within the tumour microenvironment and increased programmed death ligand 1 expression. Inactivation of either programmed death ligand 1 or IFNGR1 elicited a robust anti-tumour and/or anti-metastatic effect. A positive correlation between ELF5 and FBXW7 expression and a negative correlation between ELF5, FBXW7 and IFNGR1 expression in the tumours of patients with TNBC strongly suggest that this signalling axis could be exploited for patient stratification and immunotherapeutic treatment strategies for Elf5low patients with TNBC.

DOI: https://doi.org/10.1038/s41556-020-0495-y
Cancer Res. 2020 Apr 17. pii: canres.2660.2019. [Epub ahead of print]

Tumor cell-derived Angiopoietin-2 promotes metastasis in melanoma.

Ashik Ahmed Abdul Pari, Mahak Singhal, Corinne Hübers, Carolin Mogler, Benjamin Schieb, Anja Gampp, Nicolas Gengenbacher, Louise E Reynolds, Dorothee Terhardt, Cyrill Géraud, Jochen Utikal, Markus Thomas, Sergij Goerdt, Kairbaan M Hodivala-Dilke, Hellmut G Augustin, Moritz Felcht.

The Angiopoietin (Angpt)-TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1-TIE2 signaling to destabilize the microvasculature during pathological disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing in situ hybridization-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of melanoma patients. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell-expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced ROS production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell-expressed ANGPT2 as an autocrine positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of melanoma patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-2660
PLoS One. 2020 ;15(4): e0231711

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets.

Olga Y Korolkova, Sarrah E Widatalla, Diva S Whalen, Gladys N Nangami, Adeniyi Abimbola, Stephen D Williams, Heather K Beasley, Emily Reisenbichler, Mary Kay Washington, Josiah Ochieng, Ingrid A Mayer, Brian D Lehmann, Amos M Sakwe.

Actively growing tumors are often histologically associated with Ki67 positivity, while the detection of invasiveness relies on non-quantitative pathologic evaluation of mostly advanced tumors. We recently reported that reduced expression of the Ca2+-dependent membrane-binding annexin A6 (AnxA6) is associated with increased expression of the Ca2+ activated RasGRF2 (GRF2), and that the expression status of these proteins inversely influence the growth and motility of triple negative breast cancer (TNBC) cells. Here, we establish that the reciprocal expression of AnxA6 and GRF2 is at least in part, dependent on inhibition of non-selective Ca2+ channels in AnxA6-low but not AnxA6-high TNBC cells. Immunohistochemical staining of breast cancer tissues revealed that compared to non-TNBC tumors, TNBC tumors express lower levels of AnxA6 and higher Ki67 expression. GRF2 expression levels strongly correlated with high Ki67 in pretreatment biopsies from patients with residual disease and with residual tumor size following chemotherapy. Elevated AnxA6 expression more reliably identified patients who responded to chemotherapy, while low AnxA6 levels were significantly associated with shorter distant relapse-free survival. Finally, the reciprocal expression of AnxA6 and GRF2 can delineate GRF2-low/AnxA6-high invasive from GRF2-high/AnxA6-low rapidly growing TNBCs. These data suggest that AnxA6 may be a reliable biomarker for distant relapse-free survival and response of TNBC patients to chemotherapy, and that the reciprocal expression of AnxA6 and GRF2 can reliably delineate TNBCs into rapidly growing and invasive subsets which may be more relevant for subset-specific therapeutic interventions.

DOI: https://doi.org/10.1371/journal.pone.0231711
Theranostics. 2020 ;10(10): 4290-4307

SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression.

Zhijie Zhang, Ni Qiu, Jiang Yin, Jianlei Zhang, Hao Liu, Wei Guo, Meijun Liu, Ting Liu, Danyang Chen, Kai Luo, Hongsheng Li, Zhimin He, Jinbao Liu, Guopei Zheng.

  Background: Chemoresistance is a significant obstacle to the effective treatment of breast cancer (BC), resulting in more aggressive behavior and worse clinical outcome. The molecular mechanisms underlying breast cancer chemoresistance remain unclear. Our microarray analysis had identified the overexpression of a small molecular glycoprotein serglycin (SRGN) in multidrug-resistant BC cells. Here, we aimed to investigate the role of SRGN in chemoresistance of breast cancer and elucidate the underlying mechanisms. Methods: SRNG overexpression was identified using microarray analysis and its clinical relevance was analyzed. To investigate the role of SRGN, we performed various in vitro and in vivo studies, as well as characterization of serum and tissue samples from BC patients. Chemosensitivity measurement, gene expression interference, immunofluorescence staining, mammosphere assay, flow cytometry analysis, luciferase reporter assay, ChIP-qPCR, coimmunoprecipitation, and immunohistochemistry were performed to explore the potential functions and mechanisms of SRGN. Results: We confirmed overexpression of SRGN in chemoresistant BC cells and in serum and tissue samples from BC patients with poor response to chemotherapy. SRGN specifically predicted poor prognosis in BC patients receiving chemotherapy. Mechanistically, SRGN promoted chemoresistance both in vitro and in vivo by cross-talking with the transcriptional coactivator YES-associated protein (YAP) to maintain stemness in BC cells. Ectopic YAP expression restored the effects of SRGN knockdown. Inversely, YAP knockdown rescued the effects of SRGN overexpression. The secreted SRGN triggered ITGA5/FAK/CREB signaling to enhance YAP transcription. Reciprocally, YAP promoted SRGN transcription in a TEAD1-dependent manner to form a feed-forward circuit. Moreover, the YAP/RUNX1 complex promoted HDAC2 transcription to induce chemoresistance and stemness in BC cells. Importantly, the SRGN levels were positively correlated with the YAP and HDAC2 levels in chemoresistant BC tissues. YAP and HDAC2 acted downstream of SRNG and correlated with poor outcomes of BC patients receiving chemotherapy. Conclusions: Our findings clarify the roles and mechanisms of SRGN in mediating chemoresistance in breast cancer and suggest its use a potential biomarker for chemotherapeutic response. We believe that novel therapeutic strategies for breast cancer can be designed by targeting the signaling mediated by the crosstalk between SRGN and YAP.

Keywords:  HDAC2; SRGN; YAP; breast cancer; chemoresistance

DOI:  https://doi.org/10.7150/thno.41008
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30157-4. [Epub ahead of print]37(4): 443-455

Acquired Resistance to Immune Checkpoint Inhibitors.

Adam J Schoenfeld, Matthew D Hellmann.

  Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the characteristic durability of response to ICI, unfortunately many patients with initial response will later develop acquired resistance. The current understanding of mechanisms of acquired resistance to ICIs is remarkably limited, perhaps restraining effective development of next-generation immunotherapies. Here, we examine the barriers to progress and emerging clinical reports interrogating acquired resistance with the goal to facilitate efforts to overcome acquired resistance to ICIs in the future.

Keywords:  ICIs; acquired resistance; immunotherapy

DOI:  https://doi.org/10.1016/j.ccell.2020.03.017
J Biol Chem. 2020 Apr 16. pii: jbc.RA120.013347. [Epub ahead of print]

Genome-wide single-nucleotide resolution of oxaliplatin-DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines.

Courtney M Vaughn, Christopher P Selby, Yanyan Yang, David S Hsu, Aziz Sancar.

  Platinum-based chemotherapies, including oxaliplatin, are a mainstay in the management of solid tumors and induce cell death by forming intrastrand dinucleotide DNA adducts. Despite their common use, they are highly toxic, and approximately half of cancer patients have tumors that are either intrinsically resistant or develop resistance. Previous studies suggest that this resistance is mediated by variations in DNA repair levels or net drug influx. Here, we aimed to better define the roles of nucleotide excision repair and DNA damage in platinum chemotherapy resistance by profiling DNA damage and repair efficiency in seven oxaliplatin-sensitive and three oxaliplatin-resistant colorectal cancer cell lines. We assayed DNA repair indirectly as toxicity and directly measured bulky adduct formation and removal from the genome by slot blot and repair capacity in an excision assay, and used excision repair sequencing (XR-Seq) to map repair events genome-wide at single-nucleotide resolution. Using this combinatorial approach and proxies for oxaliplatin-DNA damage, we observed no significant differences in repair efficiency that could explain the relative sensitivities and chemotherapy resistances of these cell lines. In contrast, the levels of oxaliplatin-induced DNA damage were significantly lower in the resistant cells, indicating that decreased damage formation, rather than increased damage repair, is a major determinant of oxaliplatin resistance in these cell lines. XR-Seq-based analysis of gene expression revealed up-regulation of membrane transport pathways in the resistant cells, and these pathways may contribute to resistance. In conclusion, additional research is needed to characterize the factors mitigating cellular DNA damage formation by platinum compounds.

Keywords:  DNA damage; DNA repair; chemoresistance; chemotherapy; colorectal cancer; cytotoxicity; drug resistance; excision repair sequencing (XR-Seq); genomics; nucleotide excision repair; oxaliplatin resistance

DOI:  https://doi.org/10.1074/jbc.RA120.013347
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30150-1. [Epub ahead of print]37(4): 514-529

Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition.

Mónica Álvarez-Fernández, Marcos Malumbres.

  Inhibiting the cell-cycle kinases CDK4 and CDK6 results in significant therapeutic effect in patients with advanced hormone-positive breast cancer. The efficacy of this strategy is, however, limited by innate or acquired resistance mechanisms and its application to other tumor types is still uncertain. Here, through an integrative analysis of sensitivity and resistance mechanisms, we discuss the use of CDK4/6 inhibitors in combination with available targeted therapies, immunotherapy, or classical chemotherapy with the aim of improving future therapeutic uses of CDK4/6 inhibition in a variety of cancers.

Keywords:  breast cancer; cell-cycle kinases; cyclin-dependent kinases; resistance to cancer therapies

DOI:  https://doi.org/10.1016/j.ccell.2020.03.010
Cell. 2020 Apr 16. pii: S0092-8674(20)30346-9. [Epub ahead of print]181(2): 236-249

The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution.

Human Tumor Atlas Network

  Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Keywords:  AI; Cancer Moonshot; Human Tumor Atlas; cancer transitions; data integration; data visualization; metastasis; pre-cancer; resistance; single-cell genomics; spatial genomics; spatial imaging; tumor

DOI:  https://doi.org/10.1016/j.cell.2020.03.053
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30148-3. [Epub ahead of print]37(4): 456-470

Advancing Cancer Research and Medicine with Single-Cell Genomics.

Bora Lim, Yiyun Lin, Nicholas Navin.

  Single-cell sequencing (SCS) has impacted many areas of cancer research and improved our understanding of intratumor heterogeneity, the tumor microenvironment, metastasis, and therapeutic resistance. The development and refinement of SCS technologies has led to massive reductions in costs, increased cell throughput, and improved reproducibility, paving the way for clinical applications. However, before translational applications can be realized, there are a number of logistical and technical challenges that must be overcome. This review discusses past cancer research studies, emerging technologies, and future clinical applications that are bound to transform cancer medicine.

Keywords:  cancer evolution; intratumor heterogeneity; metastasis; single cell genomics; single cell sequencing; therapy resistance; translational genomics

DOI:  https://doi.org/10.1016/j.ccell.2020.03.008
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30149-5. [Epub ahead of print]37(4): 496-513

Overcoming Endocrine Resistance in Breast Cancer.

Ariella B Hanker, Dhivya R Sudhan, Carlos L Arteaga.

  Estrogen receptor-positive (ER+) breast cancer is the most common breast cancer subtype. Treatment of ER+ breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.

Keywords:  ESR1; SERD; SERM; aromatase inhibitor; breast cancer; endocrine resistance; estrogen receptor

DOI:  https://doi.org/10.1016/j.ccell.2020.03.009
Cancer Immunol Res. 2020 Apr 16. pii: canimm.0744.2019. [Epub ahead of print]

SHP-2 and PD-L1 inhibition combined with radiotherapy enhances systemic antitumor effects in an anti-PD-1-resistant model of non-small-cell lung cancer.

Dawei Chen, Hampartsoum B Barsoumian, Liangpeng Yang, Ahmed I Younes, Vivek Verma, Yun Hu, Hari Menon, Mark Wasley, Fatemeh Masropour, Sara Mosaffa, Tugce Ozgen, Katherine Klein, Maria Angelica Cortez, James W Welsh.

Immune checkpoint inhibitors, such as anti-PD-1/PD-L1, have emerged as promising therapies for advanced non-small-cell lung cancer (NSCLC). However, approximately 80% of patients do not respond to immunotherapy given alone because of intrinsic or acquired resistance. Radiotherapy (XRT) can overcome PD-1 resistance and improve treatment outcomes, but its efficacy remains suboptimal. The tyrosine phosphatase SHP-2, expressed in some cancers and in immune cells, has been shown to negatively affect antitumor immunity. Our hypothesis was that SHP-2 inhibition in combination with anti-PD-L1 would enhance immune-mediated responses to XRT and synergistically boost antitumor effects in an anti-PD-1-resistant mouse model. We treated 129Sv/Ev mice with anti-PD-1-resistant 344SQ NSCLC adenocarcinoma with oral SHP099 (a SHP-2 inhibitor) combined with XRT and intraperitoneal anti-PD-L1. Primary tumors were treated with XRT (3 fractions of 12 Gy each), whereas abscopal (out-of-field) tumors were observed but not treated. XRT in combination with SHP099 and anti-PD-L1 promoted local and abscopal responses, reduced lung metastases, and improved mouse survival. XRT also increased SHP-2+ M1 tumor-associated macrophages in abscopal tumors (P=0.019). The addition of SHP099 also associated with a higher M1/M2 ratio, greater numbers of CD8+ T cells, and fewer regulatory T cells. This triple-combination therapy had strong antitumor effects in a mouse model of anti-PD-1-resistant NSCLC and may be a novel therapeutic approach for anti-PD-1-resistant NSCLC in patients.

DOI: https://doi.org/10.1158/2326-6066.CIR-19-0744
Trends Cancer. 2020 Apr 08. pii: S2405-8033(20)30119-9. [Epub ahead of print]

Targeting TGFβ Signalling in Cancer: Toward Context-Specific Strategies.

Rhiannon French, Yuliang Feng, Siim Pauklin.

  The transforming growth factor beta (TGFβ) signalling pathway regulates a range of important cellular processes in a context-dependent manner. Recent discoveries have provided important insights into the regulation of the TGFβ pathway and its change from an antitumorigenic to a protumorigenic pathway. These findings may have important implications for cancer stem cell (CSC) functions and therapeutic strategies.

Keywords:  Smad2/3; TGFβ signalling pathway; cancer stem cells; epithelial-to-mesenchymal transition; gene expression; pancreatic tumorigenesis

DOI:  https://doi.org/10.1016/j.trecan.2020.03.010
Mol Cancer. 2020 Apr 15. 19(1): 76

RNA-seq reveals novel CircRNAs involved in breast cancer progression and patient therapy response.

Christophe Nicot.

DOI: https://doi.org/10.1186/s12943-020-01198-2
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30147-1. [Epub ahead of print]37(4): 471-484

Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance.

Andriy Marusyk, Michalina Janiszewska, Kornelia Polyak.

  Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often induce dramatic responses in susceptible tumors. Unfortunately, most advanced cancers, including those with robust initial responses, eventually acquire resistance to targeted therapies and relapse. Even though immune-based therapies are more likely to achieve complete cures, acquired resistance remains an obstacle to their success as well. Acquired resistance is the direct consequence of pre-existing intratumor heterogeneity and ongoing diversification during therapy, which enables some tumor cells to survive treatment and facilitates the development of new therapy-resistant phenotypes. In this review, we discuss the sources of intratumor heterogeneity and approaches to capture and account for it during clinical decision making. Finally, we outline potential strategies to improve therapeutic outcomes by directly targeting intratumor heterogeneity.

Keywords:  cancer; heterogeneity; therapeutic resistance

DOI:  https://doi.org/10.1016/j.ccell.2020.03.007
Clin Cancer Res. 2020 Apr 16. pii: clincanres.4137.2019. [Epub ahead of print]

A20 and RBX1 regulate brentuximab vedotin sensitivity in Hodgkin Lymphoma models.

Wei Wei, Yuquan Lin, Zhihui Song, Wenming Xiao, Liqi Chen, Jiejing Yin, Yan Zhou, Stefan K Barta, Michael Petrus, Thomas A Waldmann, Yibin Yang.

PURPOSE: For refractory/relapsed Hodgkin lymphoma (HL) patients (roughly 20% of total cases), few effective therapeutic options exist. Currently, Brentuximab Vedotin (BV), a drug-conjugated anti-CD30 antibody, is one of the most effective approved therapy agents for these patients. However, many patients do not achieve complete remission and ultimately develop BV-resistant disease, -necessitating a more detailed understanding of the molecular circuitry that drives BV sensitivity and the mechanism of BV resistance.
EXPERIMENTAL DESIGN: Here, we established a ubiquitin regulator-focused CRISPR library screening platform in HL and carried out a drug sensitization screen against BV to identify genes regulating BV treatment sensitivity.
RESULTS: Our CRISPR library screens revealed the ubiquitin-editing enzymes A20 and RBX1 as key molecule effectors that regulate BV sensitivity in HL line L428. A20 negatively regulates NF-κB activity which is required to prevent BV cytotoxicity. In line with these results, the RNA-seq analysis of the BV-resistant single cell clones demonstrated a consistent upregulation of NF-κB signature genes, as well as the ABC transporter gene ABCB1. Mechanically, NF-κB regulates BV treatment sensitivity through mediating ABCB1 expression. Targeting NF-κB activity synergized well with BV in killing HL cell lines, augmented BV sensitivity and overcame BV resistance in vitro and in HL xenograft mouse models.
CONCLUSIONS: Thus, our identification of this previously unrecognized mechanism provides novel knowledge of possible BV responsiveness and resistance mechanism in HL, as well as leads to promising hypothesis for the development of therapeutic strategies to overcome BV resistance in this disease.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-4137
Nat Rev Mol Cell Biol. 2020 Apr 16.

Guidelines and definitions for research on epithelial-mesenchymal transition.

EMT International Association (TEMTIA)

Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.

DOI: https://doi.org/10.1038/s41580-020-0237-9
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30152-5. [Epub ahead of print]37(4): 485-495

Liquid Biopsy-Based Biomarkers of Treatment Response and Resistance.

Elaine Kilgour, Dominic G Rothwell, Ged Brady, Caroline Dive.

  Predictive biomarkers aid selection of personalized therapy targeted to molecular alterations within an individual's tumor. Patients' responses to targeted therapies are commonly followed by treatment resistance. Here, we survey liquid biopsies as alternatives to tumor biopsies to assess predictive and therapy response biomarkers. We examine the potential of liquid biopsies to meet the challenges of minimal residual disease monitoring after curative intent treatment for earlier detection of disease recurrence. We focus on blood, the most commonly collected minimally invasive clinical sample, and on the two most widely studied assays, circulating tumor DNA and circulating tumor cells.

Keywords:  circulating tumor DNA; circulating tumor cells; liquid biopsy; minimal residual disease monitoring; personalized cancer medicine; predictive biomarkers; sensitivity and specificity; targeted and immunotherapy; treatment resistance; treatment response biomarkers

DOI:  https://doi.org/10.1016/j.ccell.2020.03.012
Theranostics. 2020 ;10(10): 4437-4452

PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression.

Ming Liu, Bing Yao, Tao Gui, Chan Guo, Xiaobin Wu, Jiahuang Li, Lingling Ma, Yexuan Deng, Peipei Xu, Ying Wang, Dongjun Yang, Qixiang Li, Xiangwei Zeng, Xinyu Li, Ruifeng Hu, Jingru Ge, Zenong Yu, Yugen Chen, Bing Chen, Junyi Ju, Quan Zhao.

  The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional repression of c-Myc target genes in gastric cancer. Methods: Immunohistochemistry was used to evaluate the expression of PRMT5, c-Myc and target genes in gastric cancer patients. PRMT5 and c-Myc interaction was assessed by immunofluorescence, co-immunoprecipitation and GST pull-down assays. Bioinformatics analysis, immunoblotting, real-time PCR, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Results: We found that c-Myc directly interacts with protein arginine methyltransferase 5 (PRMT5) to transcriptionally repress the expression of a cohort of genes, including PTEN, CDKN2C (p18INK4C), CDKN1A (p21CIP1/WAF1), CDKN1C (p57KIP2) and p63, to promote gastric cancer cell growth. Specifically, we found that PRMT5 was required to promote gastric cancer cell growth in vitro and in vivo, and for transcriptional repression of this cohort of genes, which was dependent on its methyltransferase activity. Consistently, the promoters of this gene cohort were enriched for both PRMT5-mediated symmetric di-methylation of histone H4 on Arg 3 (H4R3me2s) and c-Myc, and c-Myc depletion also upregulated their expression. H4R3me2s also colocalized with the c-Myc-binding E-box motif (CANNTG) on these genes. We show that PRMT5 directly binds to c-Myc, and this binding is required for transcriptional repression of the target genes. Both c-Myc and PRMT5 expression levels were upregulated in primary human gastric cancer tissues, and their expression levels inversely correlated with clinical outcomes. Conclusions: Taken together, our study reveals a novel mechanism by which PRMT5-dependent transcriptional repression of c-Myc target genes is required for gastric cancer progression, and provides a potential new strategy for therapeutic targeting of gastric cancer.

Keywords:  PRMT5; c-Myc; gastric cancer; histone arginine methylation; tumorigenesis

DOI:  https://doi.org/10.7150/thno.42047
Theranostics. 2020 ;10(10): 4627-4643

SLFN11 inhibits hepatocellular carcinoma tumorigenesis and metastasis by targeting RPS4X via mTOR pathway.

Chenhao Zhou, Chunxiao Liu, Wenjie Liu, Wanyong Chen, Yirui Yin, Chia-Wei Li, Jennifer L Hsu, Jialei Sun, Qiang Zhou, Hui Li, Bo Hu, Peiyao Fu, Manar Atyah, Qianni Ma, Yang Xu, Qiongzhu Dong, Mien-Chie Hung, Ning Ren.

  Hepatocellular carcinoma (HCC) remains one of the most refractory malignancies worldwide. Schlafen family member 11 (SLFN11) has been reported to play an important role in inhibiting the production of human immunodeficiency virus 1 (HIV-1). However, whether SLFN11 also inhibits hepatitis B virus (HBV), and affects HBV-induced HCC remain to be systematically investigated. Methods: qRT-PCR, western blot and immunohistochemical (IHC) staining were conducted to investigate the potential role and prognostic value of SLFN11 in HCC. Then SLFN11 was stably overexpressed or knocked down in HCC cell lines. To further explore the potential biological function of SLFN11 in HCC, cell counting kit-8 (CCK-8) assays, colony formation assays, wound healing assays and transwell cell migration and invasion assays were performed in vitro. Meanwhile, HCC subcutaneous xenograft tumor models were established for in vivo assays. Subsequently, immunoprecipitation (IP) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses were applied to understand the molecular mechanisms of SLFN11 in HCC. Co-IP, immunofluorescence and IHC staining were used to analyze the relationship between ribosomal protein S4 X-linked (RPS4X) and SLFN11. Finally, the therapeutic potential of SLFN11 with mTOR pathway inhibitor INK128 on inhibiting HCC growth and metastasis was evaluated in vitro and in vivo orthotopic xenograft mouse models. Results: We demonstrate that SLFN11 expression is decreased in HCC, which is associated with shorter overall survival and higher recurrence rates in patients. In addition, we show that low SLFN11 expression is associated with aggressive clinicopathologic characteristics. Moreover, overexpression of SLFN11 inhibits HCC cell proliferation, migration, and invasion, facilitates apoptosis in vitro, and impedes HCC growth and metastasis in vivo, all of which are attenuated by SLFN11 knockdown. Mechanistically, SLFN11 physically associates with RPS4X and blocks the mTOR signaling pathway. In orthotopic mouse models, overexpression of SLFN11 or inhibition of mTOR pathway inhibitor by INK128 reverses HCC progression and metastasis. Conclusions: SLFN11 may serve as a powerful prognostic biomarker and putative tumor suppressor by suppressing the mTOR signaling pathway via RPS4X in HCC. Our study may therefore offer a novel therapeutic strategy for treating HCC patients with the mTOR pathway inhibitor INK128.

Keywords:  Schlafen family member 11; hepatocellular carcinoma; mTOR inhibitor; prognostic biomarker; ribosomal protein S4 X-linked

DOI:  https://doi.org/10.7150/thno.42869
Cancer Discov. 2020 Apr 17.

Drug-Induced Senescence Exposes Pancreatic Cancer Vulnerabilities.

Drug-induced pancreatic cancer cell senescence increased vulnerability to chemo- and immunotherapy.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2020-057
Cancer Discov. 2020 Apr 17.

Immunotherapy Is Active in MMR-Deficient and MMR-Proficient Colon Cancer.

Neoadjuvant immunotherapy was safe and showed evidence of efficacy in stage I-III colon cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2020-058
Nat Med. 2020 Apr 13.

Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy.

Eva Pérez-Guijarro, Howard H Yang, Romina E Araya, Rajaa El Meskini, Helen T Michael, Suman Kumar Vodnala, Kerrie L Marie, Cari Smith, Sung Chin, Khiem C Lam, Andres Thorkelsson, Anthony J Iacovelli, Alan Kulaga, Anyen Fon, Aleksandra M Michalowski, Willy Hugo, Roger S Lo, Nicholas P Restifo, Shyam K Sharan, Terry Van Dyke, Romina S Goldszmid, Zoe Weaver Ohler, Maxwell P Lee, Chi-Ping Day, Glenn Merlino.

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.

DOI: https://doi.org/10.1038/s41591-020-0818-3
Oncogene. 2020 Apr 14.

The phosphorylation of CD147 by Fyn plays a critical role for melanoma cells growth and metastasis.

Xu Zhang, Zunnan Huang, Yeye Guo, Ta Xiao, Ling Tang, Shuang Zhao, Lisha Wu, Juan Su, Weiqi Zeng, Hongbin Huang, Zheng Li, Juan Tao, Jianda Zhou, Xiang Chen, Cong Peng.

CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a transmembrane glycoprotein that is highly expressed in tumor cells, particularly melanoma cells, and plays critical roles in tumor cell metastasis through the regulation of matrix metalloprotease (MMP) expression. In this study, we identified Fyn as a novel interacting protein of CD147. Fyn is a member of the Src family of nonreceptor tyrosine kinases that regulates diverse physiological processes, such as T lymphocyte differentiation, through the TCR signaling pathway. Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Two phosphospecific antibodies against Y140 and Y183 were developed to validate the phosphorylation of CD147 by Fyn. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. In addition, CD147-FF significantly blocked MMP-9 expression as well as cell migration. Moreover, we found that Fyn is overexpressed in clinical melanoma tissues as well as in melanoma cell lines. Knockdown of Fyn expression markedly attenuated the malignant phenotype of melanoma cells in vitro and in vivo through downregulation of CD147 phosphorylation, indicating that Fyn/CD147 is a potential target molecule in melanoma treatment. Finally, through virtual screening, we identified amodiaquine as a potential inhibitor targeting the Fyn/CD147 axis. Amodiaquine treatment dramatically inhibited the phosphorylation of CD147 by Fyn, thus attenuating melanoma cell growth and invasion in vitro and in vivo, suggesting that amodiaquine is a promising inhibitor for melanoma treatment.

DOI: https://doi.org/10.1038/s41388-020-1287-3
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30146-X. [Epub ahead of print]37(4): 530-542

Response and Resistance to BCR-ABL1-Targeted Therapies.

Theodore P Braun, Christopher A Eide, Brian J Druker.

  Chronic myeloid leukemia (CML), caused by constitutively active BCR-ABL1 fusion tyrosine kinase, has served as a paradigm for successful application of molecularly targeted cancer therapy. The development of the tyrosine kinase inhibitor (TKI) imatinib allows patients with CML to experience near-normal life expectancy. Specific point mutations that decrease drug binding affinity can produce TKI resistance, and second- and third-generation TKIs largely mitigate this problem. Some patients develop TKI resistance without known resistance mutations, with significant heterogeneity in the underlying mechanism, but this is relatively uncommon, with the majority of patients with chronic phase CML achieving long-term disease control. In contrast, responses to TKI treatment are short lived in advanced phases of the disease or in BCR-ABL1-positive acute lymphoblastic leukemia, with relapse driven by both BCR-ABL1 kinase-dependent and -independent mechanisms. Additionally, the frontline CML treatment with second-generation TKIs produces deeper molecular responses, driving disease burden below the detection limit for a greater number of patients. For patients with deep molecular responses, up to half have been able to discontinue therapy. Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation.

Keywords:  BCR-ABL; CML; targeted therapy; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.ccell.2020.03.006
J Natl Cancer Inst. 2020 Apr 15. pii: djaa052. [Epub ahead of print]

Pathological tumor response following immune checkpoint blockade for deficient mismatch repair advanced colorectal cancer.

Kaysia Ludford, Romain Cohen, Magali Svrcek, Wai Chin Foo, Raphael Colle, Yann Parc, Jane Varkey Thomas, Van Karlyle Morris, Scott Kopetz, George J Chang, Michael Overman, Thierry Andre.

Immune checkpoint inhibition (CPI) for metastatic colorectal cancer (mCRC) with deficient mismatch repair (dMMR) demonstrates high clinical activity that appears durable but the impact of CPI on pathological tumor response is unknown. In this retrospective analysis, our objective was to assess pathological response and clinical outcomes in dMMR mCRC patients treated with CPI prior to surgical resection of primary and/or metastatic tumor. Amongst 121 advanced dMMR mCRC patients treated with CPI at two institutions between November 2016 and December 2018, 14 underwent surgery. Pathologic complete response was noted in the resected specimens of 13 patients despite the presence of residual tumor on pre-operative imaging in 12 of those patients. With median follow-up of 9 months, no patients have had disease relapse or progression. For this small retrospective study, the data suggests that residual radiographic tumor may not require systematic resection following response to anti-PD1 based therapy. However, larger prospective studies are warranted.

DOI: https://doi.org/10.1093/jnci/djaa052
Cancer Res. 2020 Apr 14. pii: canres.3230.2019. [Epub ahead of print]

Targeting p63 upregulation abrogates resistance to MAPK inhibitors in melanoma.

Ankit Patel, Lucia Fraile Garcia, Viviana Mannella, Luke Gammon, Tiffanie-Marie Borg, Tania Maffucci, Maria Scatolini, Giovanna Chiorino, Elisabetta Vergani, Monica Rodolfo, Andrea Maurichi, Christian Posch, Rubeta Nishat Matin, Catherine A Harwood, Daniele Bergamaschi.

Targeting the MAPK pathway by combined inhibition of BRAF and MEK has increased overall survival in advanced BRAF-mutant melanoma in both therapeutic and adjuvant clinical settings. However, a significant proportion of tumors develop acquired resistance, leading to treatment failure. We have previously shown p63 to be an important inhibitor of p53-induced apoptosis in melanoma following genotoxic drug exposure. Here we investigated the role of p63 in acquired resistance to MAPK inhibition and show that p63 isoforms are upregulated in melanoma cell lines chronically exposed to BRAF and MEK inhibition, with consequent increased resistance to apoptosis. This p63 upregulation was the result of its reduced degradation by the E3 ubiquitin ligase FBXW7. FBXW7 was itself regulated by MDM2, and in therapy-resistant melanoma cell lines, nuclear accumulation of MDM2 caused downregulation of FBXW7 and consequent upregulation of p63. Consistent with this, both FBXW7 inactivating mutations and MDM2 upregulation were found in melanoma clinical samples. Treatment of MAPK inhibitor-resistant melanoma cells with MDM2 inhibitor Nutlin-3A restored FBXW7 expression and p63 degradation in a dose-dependent manner and sensitized these cells to apoptosis. Collectively, these data provide a compelling rationale for future investigation of nutlin-3A as an approach to abrogate acquired resistance of melanoma to MAPK inhibitor targeted therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3230
Theranostics. 2020 ;10(10): 4395-4409

circPRRC2A promotes angiogenesis and metastasis through epithelial-mesenchymal transition and upregulates TRPM3 in renal cell carcinoma.

Wei Li, Feng-Qiang Yang, Chen-Min Sun, Jian-Hua Huang, Hai-Min Zhang, Xue Li, Guang-Chun Wang, Ning Zhang, Jian-Ping Che, Wen-Tao Zhang, Yang Yan, Xu-Dong Yao, Bo Peng, Jun-Hua Zheng, Min Liu.

  Background: Circular RNAs (circRNAs) have been identified as essential regulators in a plethora of cancers. Nonetheless, the mechanistic functions of circRNAs in Renal Cell Carcinoma (RCC) remain largely unknown. Methods: In this study, we aimed to identify novel circRNAs that regulate RCC epithelial-mesenchymal transition (EMT), and to subsequently determine their regulatory mechanisms and clinical significance. Results: circPRRC2A was identified by circRNA microarray and validated by qRT-PCR. The role of circPRRC2A in RCC metastasis was evaluated both in vitro and in vivo. We found that increased expression of circPRRC2A is positively associated with advanced clinical stage and worse survivorship in RCC patients. Mechanistically, our results indicate that circPRRC2A prevents the degradation of TRPM3, a tissue-specific oncogene, mRNA by sponging miR-514a-5p and miR-6776-5p. Moreover, circPRRC2A promotes tumor EMT and aggressiveness in patients with RCC. Conclusions: These findings infer the exciting possibility that circPRRC2A may be exploited as a therapeutic and prognostic target for RCC patients.

Keywords:  RCC; circPRRC2A; circular RNA; lung metastasis; therapeutic target

DOI:  https://doi.org/10.7150/thno.43239
Lancet Oncol. 2020 Apr 09. pii: S1470-2045(20)30231-X. [Epub ahead of print]

CAR T-cell therapy for relapsed or refractory mantle-cell lymphoma.

Robert Stirrups.

DOI: https://doi.org/10.1016/S1470-2045(20)30231-X
EMBO Mol Med. 2020 Apr 17. e11164

Preclinical validation of a novel metastasis-inhibiting Tie1 function-blocking antibody.

Mahak Singhal, Nicolas Gengenbacher, Silvia La Porta, Stephanie Gehrs, Jingjing Shi, Miki Kamiyama, Diane M Bodenmiller, Anthony Fischl, Benjamin Schieb, Eva Besemfelder, Sudhakar Chintharlapalli, Hellmut G Augustin.

  The angiopoietin (Ang)-Tie pathway has been intensely pursued as candidate second-generation anti-angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2-targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelial-specific genetic deletion has previously been shown to result in a strong reduction in metastatic growth. Here, we report a novel Tie1 function-blocking antibody (AB-Tie1-39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of AB-Tie1-39 strongly impeded systemic metastasis. Furthermore, the administration of AB-Tie1-39 in a perioperative therapeutic window led to a significant survival advantage as compared to control-IgG-treated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that AB-Tie1-39 treatment suppressed tumor cell extravasation at secondary sites. Taken together, the data phenocopy previous genetic work in endothelial Tie1 KO mice and thereby validate AB-Tie1-39 as a Tie1 function-blocking antibody. The study establishes Tie1 as a therapeutic target for metastasis in a perioperative or neoadjuvant setting.

Keywords:  angiogenesis; angiopoietin-Tie signaling; cancer; endothelial cells; metastasis

DOI:  https://doi.org/10.15252/emmm.201911164
Clin Cancer Res. 2020 Apr 17. pii: clincanres.0426.2020. [Epub ahead of print]

Phase II Study of Ensituximab, a Novel Chimeric Monoclonal Antibody, in Adults with Unresectable, Metastatic Colorectal Cancer.

Richard D Kim, Nilofer S Azad, Michael A Morse, Elizabeth Poplin, Amit Mahipal, Benjamin Tan, Sharon A Mavroukakis, Massimo Fantini, Kwong Y Tsang, Anjum Zaki, Jose Torrealba, Philip M Arlen, Muhammad S Beg.

PURPOSE: Patients with metastatic colorectal cancer (CRC) refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric monoclonal antibody targeting a variant of MUC5AC with specificity to CRC.
PATIENTS AND METHODS: Single arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed MUC5AC antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required based on the assumption that ensituximab would improve median overall survival by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients.
RESULTS: Sixty-three patients with advanced, refractory CRC were enrolled and 53 subjects were treated in phase 2 arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment related adverse events at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%) and diarrhea (6%). Serious adverse events at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin and hypoxia. No patients discontinued treatment due to drug related adverse events.
CONCLUSIONS: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory CRC.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-0426
Cancer Cell. 2020 Apr 13. pii: S1535-6108(20)30154-9. [Epub ahead of print]37(4): 431-442

Toward a More Precise Future for Oncology.

Yonina R Murciano-Goroff, Barry S Taylor, David M Hyman, Alison M Schram.

  Prospective molecular characterization of cancer has enabled physicians to define the genomic changes of each patient's tumor in real time and select personalized therapies based on these detailed portraits. Despite the promise of such an approach, previously unrecognized biological and therapeutic complexity is emerging. Here, we synthesize lessons learned and discuss the steps required to extend the benefits of genome-driven oncology, including proposing strategies for improved drug design, more nuanced patient selection, and optimized use of available therapies. Finally, we suggest ways that next-generation genome-driven clinical trials can evolve to accelerate our understanding of cancer biology and improve patient outcomes.

Keywords:  clinical trial design; drug development; genome-driven oncology; precision oncology

DOI:  https://doi.org/10.1016/j.ccell.2020.03.014
Clin Cancer Res. 2020 Apr 16. pii: clincanres.3637.2019. [Epub ahead of print]

Patient-derived organoids from multiple colorectal cancer liver metastases reveal moderate intra-patient pharmacotranscriptomic heterogeneity.

Jarle Bruun, Kushtrim Kryeziu, Peter W Eide, Seyed H Moosavi, Ina A Eilertsen, Jonas Langerud, Bård I Røsok, Max Z Totland, Tuva Høst Brunsell, Teijo Pellinen, Jani Saarela, Christian H Bergsland, Hector G Palmer, Kristoffer W Brudvik, Tormod Guren, Rodrigo Dienstmann, Marianne G Guren, Arild Nesbakken, Bjørn Atle Bjørnbeth, Anita Sveen, Ragnhild A Lothe.

PURPOSE: Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer (CRC).
EXPERIMENTAL DESIGN: We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDOs) from resected CRC liver metastases. Drug sensitivity testing (n=40 clinically relevant agents) and gene expression profiling were performed of thirty-nine metastases from twenty-two patients.
RESULTS: Three drug response clusters were identified among the CRC metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2-5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression.
CONCLUSIONS: Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic CRC. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression-based predictive signatures to guide experimental therapies.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-3637
Trends Cell Biol. 2020 Apr 14. pii: S0962-8924(20)30058-1. [Epub ahead of print]

The Complex Interplay between Antioxidants and ROS in Cancer.

Isaac S Harris, Gina M DeNicola.

  Reactive oxygen species (ROS) play important roles in tissue homeostasis, cellular signaling, differentiation, and survival. In this review, we discuss the types of ROS, their impact on cellular processes, and their pro- and antitumorigenic effects. Further, we discuss recent advances in our understanding of both endogenous and exogenous antioxidants in tumorigenic processes. Finally, we discuss how aberrant activation of antioxidant programs by the transcription factor NFE2-related factor 2 (NRF2) influences tumorigenesis and metastasis, and where the current gaps in our knowledge remain.

Keywords:  NRF2; ROS; antioxidant; cancer; glutathione

DOI:  https://doi.org/10.1016/j.tcb.2020.03.002