bims-tucedo 2020-04-26 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2020–04–26
29 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells.
Polycomb-like Protein 3 induces proliferation and drug resistance in multiple myeloma and is regulated by miRNA-15a.
Mapping the spreading routes of lymphatic metastases in human colorectal cancer.
Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.
The deubiquitylase USP2 maintains ErbB2 abundance via counteracting endocytic degradation and represents a therapeutic target in ErbB2-positive breast cancer.
The premise of personalized immunotherapy for cancer dormancy.
Stromal platelet-derived growth factor receptor-β signaling promotes breast cancer metastasis in the brain.
Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone.
Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.
Tumor-neuroglia interaction promotes pancreatic cancer metastasis.
ZNF750 represses breast cancer invasion via epigenetic control of prometastatic genes.
Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche.
Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer progression.
Microtubule engagement with taxane is altered in taxane-resistant gastric cancer.
Letter phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma.
Spatiotemporal regulation of ∆Np63 by TGFβ-regulated miRNAs is essential for cancer metastasis.
Targeting the interaction between RNA-binding protein HuR and FOXQ1 suppresses breast cancer invasion and metastasis.
The EZH2-PHACTR2-AS1-ribosome axis induces genomic instability and promotes growth and metastasis in breast cancer.
A catalogue of cancer-driving mutations in healthy tissue.
Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells.
LGR5 marks targetable tumor-initiating cells in mouse liver cancer.
Longitudinal monitoring of ctDNA in patients with melanoma and brain metastases treated with immune checkpoint inhibitors.
Dendritic cells, the T cell-inflamed tumor microenvironment and immunotherapy treatment response.
HER3 targeting with an antibody-drug conjugate bypasses resistance to anti-HER2 therapies.
Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition.
Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation.
Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination With Fulvestrant in Patients With AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.
HuR/ELAVL1 drives malignant peripheral nerve sheath tumour growth and metastasis.
Stromal deactivation by CSF1: a new feature of the aggressive pancreatic cancer microenvironment.

Clin Cancer Res. 2020 Apr 22. pii: clincanres.0269.2020. [Epub ahead of print]

AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells.

Riley A Hampsch, Jason D Wells, Nicole A Traphagen, Charlotte F McCleery, Jennifer L Fields, Kevin Shee, Lloye M Dillon, Darcy B Pooler, Lionel D Lewis, Eugene Demidenko, Yina H Huang, Jonathan D Marotti, Abigail E Goen, William B Kinlaw, Todd W Miller.

PURPOSE: Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies.
EXPERIMENTAL DESIGN: Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy.
RESULTS: Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the anti-diabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival.
CONCLUSIONS: AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-0269
Mol Cancer Res. 2020 Apr 20. pii: molcanres.0852.2019. [Epub ahead of print]

Polycomb-like Protein 3 induces proliferation and drug resistance in multiple myeloma and is regulated by miRNA-15a.

Tengteng Yu, Chenxing Du, Xiaoke Ma, Weiwei Sui, Zhen Yu, Lanting Liu, Lei Zhao, Zhongqing Li, Jie Xu, Xiaojing Wei, Wen Zhou, Shuhui Deng, Dehui Zou, Gang An, Yu-Tzu Tai, Guido Tricot, Kenneth C Anderson, Lugui Qiu, Fenghuang Zhan, Mu Hao.

Multiple myeloma (MM) remains incurable due to the persistence of a minor population of MM cells that exhibit drug resistance, which leads to relapse and refractory MM. Elucidating the mechanism underlying drug resistance and developing an effective treatment are critical for clinical management of MM. Here we showed that promoting expression of the gene for polycomb-like protein 3 (PHF19) induced MM cell growth and multi-drug resistance in vitro and in vivo. PHF19 was overexpressed in high-risk and drug-resistant primary cells from patients. High levels of PHF19 were correlated with inferior survival of MM patients, in the total therapy 2 (TT2) cohort and in the Intergroup Francophone du Myeloma (IFM) cohort. Enhancing PHF19 expression levels increased Bcl-xL, MCL-1 and HIF-1a expression in MM cells. PHF19 also bound directly with EZH2 and promoted the phosphorylation of EZH2 through PDK1/AKT signaling. miR-15a is a small non-coding RNA that targeted the 3'UTR of PHF19. We found that downregulation of miR-15a led to high levels of PHF19 in MM cells. These findings revealed that PHF19 served a crucial role in MM proliferation and drug resistance and suggested that the miR-15a/PHF19/EZH2 pathway made a pivotal contribution to MM pathogenesis, offering a promising approach to MM treatment. Implications: Our findings identify that PHF19 mediates EZH2 phosphorylation as a mechanism of myeloma cell drug resistance, providing a rationale to explore therapeutic potential of targeting PHF19 in relapsed or refractory MM patients.

DOI: https://doi.org/10.1158/1541-7786.MCR-19-0852
Nat Commun. 2020 Apr 24. 11(1): 1993

Mapping the spreading routes of lymphatic metastases in human colorectal cancer.

Chong Zhang, Lin Zhang, Tianlei Xu, Ruidong Xue, Liang Yu, Yuelu Zhu, Yunlong Wu, Qingqing Zhang, Dongdong Li, Shuohao Shen, Dongfeng Tan, Fan Bai, Haizeng Zhang.

Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). How tumor cells disseminate within the lymphatic network remains largely unknown. Here, we analyze the subclonal structure of 94 tumor samples, covering the primary tumors, lymph node metastases (LNMs), and liver metastases from 10 CRC patients. We portray a high-resolution lymphatic metastatic map for CRC by dividing LNMs into paracolic, intermediate, and central subgroups. Among the 61 metastatic routes identified, 38 (62.3%) are initiated from the primary tumors, 22 (36.1%) from LNMs, and 1 from liver metastasis (1.6%). In 5 patients, we find 6 LNMs that reseed 2 or more LNMs. We summarize 3 diverse modes of metastasis in CRC and show that skip spreading of tumor cells within the lymphatic network is common. Our study sheds light on the complicated metastatic pattern in CRC and has great clinical implications.

DOI: https://doi.org/10.1038/s41467-020-15886-6
Nat Commun. 2020 Apr 21. 11(1): 1923

Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.

Ahmet Acar, Daniel Nichol, Javier Fernandez-Mateos, George D Cresswell, Iros Barozzi, Sung Pil Hong, Nicholas Trahearn, Inmaculada Spiteri, Mark Stubbs, Rosemary Burke, Adam Stewart, Giulio Caravagna, Benjamin Werner, Georgios Vlachogiannis, Carlo C Maley, Luca Magnani, Nicola Valeri, Udai Banerji, Andrea Sottoriva.

Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.

DOI: https://doi.org/10.1038/s41467-020-15596-z
Cell Death Differ. 2020 Apr 23.

The deubiquitylase USP2 maintains ErbB2 abundance via counteracting endocytic degradation and represents a therapeutic target in ErbB2-positive breast cancer.

Jinrui Zhang, Shuyan Liu, Qiong Li, Yulin Shi, Yueguang Wu, Fang Liu, Shanshan Wang, Mohamed Y Zaky, Waleed Yousuf, Qianhui Sun, Dong Guo, Taishu Wang, Yingqiu Zhang, Yang Wang, Man Li, Han Liu.

ErbB2 overexpression identifies a subclass of breast cancer as ErbB2-positive that is frequently associated with poor prognosis. Current ErbB2-targeted therapies have profoundly improved patient outcomes, but mutations occurring in ErbB2 have been shown to confer drug resistance. Induction of ErbB2 degradation was proposed as an intriguing strategy to battle with ErbB2-positive breast cancer and reduced mutation-incurred drug resistance. Although multiple HSP90 inhibitors have been demonstrated to effectively trigger ErbB2 degradation, none succeeded in the clinical evaluations. To develop novel ErbB2-targeting strategies, we investigated the endocytic degradation and reversible ubiquitylation of ErbB2 in breast cancer. In this study, we reveal that HSP90 inhibition leads to efficient ubiquitylation and endocytic degradation of ErbB2 through the canonical endo-lysosomal route. USP2 associates with internalized ErbB2 and prevents its lysosomal sorting and degradation via exerting deubiquitylase activity. Accordingly, the USP2 inhibitor ML364 is capable of inducing ErbB2 ubiquitylation and accelerating its turnover. ML364 potentiates the pro-degradation effects of HSP90 inhibitors on ErbB2 and hence sensitizes ErbB2-positive breast cancer cells to HSP90 inhibition. The combination of USP2 and HSP90 inhibitors effectively restrains ErbB2-positive breast cancer xenograft growth in vivo. Based on these observations, we conclude that USP2 safeguards ErbB2 surface levels by antagonizing its ubiquitylation-mediated endocytic degradation, which can be exploited to design novel therapeutic strategies against ErbB2-driven malignancies as combinatorial treatment with HSP90 inhibitors.

DOI: https://doi.org/10.1038/s41418-020-0538-8
Oncogene. 2020 Apr 22.

The premise of personalized immunotherapy for cancer dormancy.

Masoud H Manjili.

Progress in cancer therapies has resulted in improved survival of patients with early stage breast cancer. However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment of early stage breast cancer. To this end, tumor recurrences have been attributed to the presence of dormant tumor cells in breast cancer patients and cancer survivors. Current clinical practice guidelines recommend a "wait-and-watch" approach for tumor recurrence. This is because of our limited understanding of tumor dormancy. Dormant tumor cells are quiescent, and thus, do not respond to chemotherapies or radiation therapies, and they are not operable. Therefore, immunotherapy is the only option for the treatment of tumor dormancy. However, gaps in our knowledge as to dormancy-specific antigens prevent a relapse preventing vaccine design. Here, I provide a critical review of cancer immunotherapy, and discuss empirical evidence related to naturally occurring tumor dormancy and treatment-induced tumor dormancy at the site of primary tumor and in distant organs before and after cancer therapies. Finally, I suggest that personalized vaccines targeting dormancy-associated neoantigens, which can be given to patients with early stage disease after the completion of neoadjuvant therapies and tumor resection as well as to cancer survivors could eliminate relapse causing dormant cells and offer a cure for cancer.

DOI: https://doi.org/10.1038/s41388-020-1295-3
Cancer Res. 2020 Apr 23. pii: canres.3731.2019. [Epub ahead of print]

Stromal platelet-derived growth factor receptor-β signaling promotes breast cancer metastasis in the brain.

Katie A Thies, Anisha M Hammer, Blake E Hildreth, Sarah A Steck, Jonathan M Spehar, Raleigh D Kladney, Jennifer M Geisler, Manjusri Das, Luke O Russell, Jerome F Bey, Chelsea M Bolyard, Robert Pilarski, Anthony J Trimboli, Maria C Cuitiño, Christopher S Koivisto, Daniel G Stover, Lynn Schoenfield, Jose Otero, Jonathan Godbout, Arnab Chakravarti, Matthew D Ringel, Bhuvaneswari Ramaswamy, Zaibo Li, Balveen Kaur, Gustavo Leone, Michael C Ostrowski, Steven T Sizemore, Gina M Sizemore.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stromal signaling mediates breast cancer (BC) initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway mediates both primary tumor growth and metastasis; specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβD849V) exerted pro-proliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβD849V also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβD849V was observed within a subset of astrocytes, and aged mice expressing PDGFRβD849V exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβD849V in their stromal cells as a preclinical model of BC-associated brain metastases (BCBM) and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with BC.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3731
EMBO Rep. 2020 Apr 21. e50162

Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone.

Katie L Owen, Linden J Gearing, Damien J Zanker, Natasha K Brockwell, Weng Hua Khoo, Daniel L Roden, Marek Cmero, Stefano Mangiola, Matthew K Hong, Alex J Spurling, Michelle McDonald, Chia-Ling Chan, Anupama Pasam, Ruth J Lyons, Hendrika M Duivenvoorden, Andrew Ryan, Lisa M Butler, John M Mariadason, Tri Giang Phan, Vanessa M Hayes, Shahneen Sandhu, Alexander Swarbrick, Niall M Corcoran, Paul J Hertzog, Peter I Croucher, Chris Hovens, Belinda S Parker.

  The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.

Keywords:  bone metastasis; dormancy; immune evasion; prostate cancer; type I interferon

DOI:  https://doi.org/10.15252/embr.202050162
Oncogene. 2020 Apr 19.

Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.

Sunil Pancholi, Ricardo Ribas, Nikiana Simigdala, Eugene Schuster, Joanna Nikitorowicz-Buniak, Anna Ressa, Qiong Gao, Mariana Ferreira Leal, Amandeep Bhamra, Allan Thornhill, Ludivine Morisset, Elodie Montaudon, Laura Sourd, Martin Fitzpatrick, Maarten Altelaar, Stephen R Johnston, Elisabetta Marangoni, Mitch Dowsett, Lesley-Ann Martin.

Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of 'classical' oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M-checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER and RB1 CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition.

DOI: https://doi.org/10.1038/s41388-020-1284-6
Theranostics. 2020 ;10(11): 5029-5047

Tumor-neuroglia interaction promotes pancreatic cancer metastasis.

Dan Su, Xiaofeng Guo, Leyi Huang, Huilin Ye, Zhiguo Li, Longfa Lin, Rufu Chen, Quanbo Zhou.

  Rationale: The peripheral nervous system (PNS) plays an important role in tumor growth and progression. Schwann cells (SCs), the main glia cells of the PNS, augment cancer metastasis in contact-dependent or contact-independent manner in various malignancies. In the present study, we aimed to determine whether interplay between pancreatic cancer cells and SCs via paracrine signaling contributes to cancer progression. Methods: Immunofluorescence analysis was performed to reveal the distribution of SCs in PDAC tissues and to determine the prognostic value and clinicopathological relevance of the level of intra‑tumoral SC markers for patients diagnosed with PDAC. Transwell assays and wound healing assays were carried out to investigate the influence of SC conditioned medium (SCM), SC co‑culture, or co-cultured CM on the migratory and invasive abilities of pancreatic cancer cells. The mechanism of SCs induced cancer cells migration and invasion was confirmed using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assays (ELISAs), western blotting, immunofluorescence, immunohistochemistry, siRNA-mediated gene interference, and an in vivo mouse model. Results: Immunofluorescence analysis of tissue samples revealed that there were two different types of SCs distributed in the tumor microenvironment, the presence of which correlated with several clinicopathological characteristics and overall survival for patients with PDAC. Although SCM had no impact on the motility and invasiveness of tumor cells, both co-cultivation with SCs and co‑cultured CM enhanced pancreatic cancer cell migration and invasion. Mechanistically, SC‑derived Interleukin 6 (IL6), which was induced by co-culture with pancreatic cancer cells, augmented cancer cell migration and invasion by activating STAT3 signaling in cancer cells, while IL6 neutralization or STAT3 downregulation abrogated these effects. Furthermore, Interleukin 1β (IL1β), secreted by tumor cells, activated the nuclear actor (NF)-kappa B pathway in SCs, resulting in increased cytokines production, including IL6, while inhibiting the IL1β-IL1R1 axis led to inactivation of NF-kappa B signaling and downregulated cytokines expression in SCs. Interfering with tumor-neuroglia crosstalk impeded cancer cell dissemination in vivo. Conclusion: Schwann cells were extensively distributed in the PDAC tumor microenvironment and high level of intra-tumoral SC markers could serve as an independent prognostic factor for poor survival of patients with PDAC. The tumor-neuroglia interaction is indispensable for SCs to acquire a tumor-facilitating phenotype. Targeting the tumor-neuroglia interplay might be a promising strategy to treat PDAC.

Keywords:  Schwann cell; epithelial-mesenchymal transition; interaction; metastasis; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.7150/thno.42440
Oncogene. 2020 Apr 20.

ZNF750 represses breast cancer invasion via epigenetic control of prometastatic genes.

Matteo Cassandri, Alessio Butera, Ivano Amelio, Anna Maria Lena, Manuela Montanaro, Alessandro Mauriello, Lucia Anemona, Eleonora Candi, Richard A Knight, Massimiliano Agostini, Gerry Melino.

Breast cancer is the second leading cause of cancer-related deaths among women, largely due to the progression of a significant fraction of primary tumours to the metastatic stage. Here, we show that zinc-finger protein 750 (ZNF750) opposes the migration and invasion of breast cancer cells by repressing a prometastatic transcriptional programme, which includes genes involved in focal adhesion and extracellular matrix interactions, such as LAMB3 and CTNNAL1. Mechanistically, ZNF750 recruits the epigenetic modifiers KDM1A and HDAC1 to the promoter regions of LAMB3 and CTNNAL1, influencing histone marks and transactivating these genomic sites. Gene expression analysis in cancer patient datasets indicated that ZNF750 and its targets were negative prognostic factors in breast cancer. Together, our findings shed light on the molecular mechanism by which ZNF750 regulates cell migration and invasion, suggesting a role in breast cancer metastasis.

DOI: https://doi.org/10.1038/s41388-020-1277-5
Nature. 2020 Apr;580(7804): 524-529

Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche.

Manolis Roulis, Aimilios Kaklamanos, Marina Schernthanner, Piotr Bielecki, Jun Zhao, Eleanna Kaffe, Laura-Sophie Frommelt, Rihao Qu, Marlene S Knapp, Ana Henriques, Niki Chalkidi, Vasiliki Koliaraki, Jing Jiao, J Richard Brewer, Maren Bacher, Holly N Blackburn, Xiaoyun Zhao, Richard M Breyer, Vassilis Aidinis, Dhanpat Jain, Bing Su, Harvey R Herschman, Yuval Kluger, George Kollias, Richard A Flavell.

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts1. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types2,3. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E2 (PGE2). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE2 drives the expansion οf a population of Sca-1+ reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1+ cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1+ cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE2-Ptger4. Analyses of patient-derived organoids established that PGE2-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE2-Ptger4-Yap signalling axis.

DOI: https://doi.org/10.1038/s41586-020-2166-3
Oncogene. 2020 Apr 20.

Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer progression.

Mingchuan Li, Jongdee Nopparat, Byron J Aguilar, Yan-Hua Chen, Jiao Zhang, Jie Du, Xin Ai, Yong Luo, Yongguang Jiang, Christi Boykin, Qun Lu.

Only a small number of genes are bona fide oncogenes and tumor suppressors such as Ras, Myc, β-catenin, p53, and APC. However, targeting these cancer drivers frequently fail to demonstrate sustained cancer remission. Tumor heterogeneity and evolution contribute to cancer resistance and pose challenges for cancer therapy due to differential genomic rearrangement and expression driving distinct tumor responses to treatments. Here we report that intratumor heterogeneity of Wnt/β-catenin modulator δ-catenin controls individual cell behavior to promote cancer. The differential intratumor subcellular localization of δ-catenin mirrors its compartmentalization in prostate cancer xenograft cultures as result of mutation-rendered δ-catenin truncations. Wild-type and δ-catenin mutants displayed distinct protein interactomes that highlight rewiring of signal networks. Localization specific δ-catenin mutants influenced p120ctn-dependent Rho GTPase phosphorylation and shifted cells towards differential bFGF-responsive growth and motility, a known signal to bypass androgen receptor dependence. Mutant δ-catenin promoted Myc-induced prostate tumorigenesis while increasing bFGF-p38 MAP kinase signaling, β-catenin-HIF-1α expression, and the nuclear size. Therefore, intratumor δ-catenin heterogeneity originated from genetic remodeling promotes prostate cancer expansion towards androgen independent signaling, supporting a neomorphism model paradigm for targeting tumor progression.

DOI: https://doi.org/10.1038/s41388-020-1281-9
Clin Cancer Res. 2020 Apr 22. pii: clincanres.3018.2019. [Epub ahead of print]

Microtubule engagement with taxane is altered in taxane-resistant gastric cancer.

Giuseppe Galletti, Chao Zhang, Ada Gjyrezi, Kyle Cleveland, Jiaren Zhang, Sarah Powell, Prashant V Thakkar, Doron Betel, Manish A Shah, Paraskevi Giannakakou.

PURPOSE: Although taxane-based therapy is standard treatment for advanced gastric cancer (GC), a majority of patients exhibit intrinsic resistance to taxanes. Here, we aim to identify the molecular basis of taxane resistance in GC.
EXPERIMENTAL DESIGN: we performed a post-hoc analysis of the TAX-325 clinical trial and molecular interrogation of GC cell lines to assess the benefit of docetaxel in diffuse (DIF-GC) vs intestinal (INT-GC) GC. We assessed drug-induced microtubule stabilization in GC cells and in biopsies of GC patients treated with taxanes. We performed transcriptome analysis in taxane-treated GC cells and patients to identify molecular drivers of taxane resistance.
RESULTS: DIF-GC patients did not derive a clinical benefit from taxane treatment suggesting intrinsic taxane resistance. DIF-GC cell lines displayed intrinsic resistance specific to taxanes due to impaired drug-induced microtubule stabilization, in the absence of tubulin mutations or decreased drug accumulation. Using taxane-treated GC patient biopsies, we demonstrated that absence of drug-target engagement was correlated with clinical taxane resistance. Taxane-sensitive cell lines displayed faster microtubule dynamics at baseline, implicating proteins that regulate cytoskeletal dynamics in intrinsic taxane resistance. Differential gene expression analysis of untreated and docetaxel-treated GC lines and patient samples identified kinesins to be associated with taxane sensitivity in vitro and in patient samples.
CONCLUSION: our data reveal that taxane-resistance is more prevalent in patients with DIF-GC, support assessment of drug-target engagement as a early read-out of taxane clinical efficacy, and encourage the investigation of kinesins and other microtubule-associated proteins as potentially targetable mediators of taxane resistance in GC.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-3018
Leukemia. 2020 Apr 21.

Letter phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma.

Hans C Lee, Noopur S Raje, Ola Landgren, Vijay V Upreti, Jin Wang, Ariel A Avilion, Xuguang Hu, Erik Rasmussen, Gataree Ngarmchamnanrith, Hisaki Fujii, Andrew Spencer.

DOI: https://doi.org/10.1038/s41375-020-0834-9
Cancer Res. 2020 Apr 20. pii: canres.2733.2019. [Epub ahead of print]

Spatiotemporal regulation of ∆Np63 by TGFβ-regulated miRNAs is essential for cancer metastasis.

Ngoc H B Bui, Marco Napoli, Andrew John Davis, Hussein A Abbas, Kimal Rajapakshe, Cristian Coarfa, Elsa R Flores.

∆Np63 is a transcription factor of the p53 family and has crucial functions in normal development and disease. The expression pattern of ∆Np63 in human cancer suggests dynamic regulation of this isoform during cancer progression and metastasis. Many primary and metastatic tumors express high levels of ∆Np63, while ∆Np63 loss is crucial for tumor dissemination, indicating an oscillatory expression of ∆Np63 during cancer progression. Here we use genetically engineered orthotopic mouse models of breast cancer to show that while depletion of ΔNp63 inhibits primary mammary adenocarcinoma development, oscillatory expression of ΔNp63 in established tumors is crucial for metastatic dissemination in breast cancer. A TGFβ-regulated microRNA network acted as upstream regulators of this oscillatory expression of ΔNp63 during cancer progression. This work sheds light on the pleiotropic roles of ∆Np63 in cancer and unveils critical functions of TGFβ in the metastatic process.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-2733
Commun Biol. 2020 Apr 24. 3(1): 193

Targeting the interaction between RNA-binding protein HuR and FOXQ1 suppresses breast cancer invasion and metastasis.

Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Shuang Han, Cuncong Zhong, Rebecca T Marquez, Lanjing Wei, Spencer Wood, Sudeshna Roy, Ragul Gowthaman, John Karanicolas, Fei P Gao, Dan A Dixon, Danny R Welch, Ling Li, Min Ji, Jeffrey Aubé, Liang Xu.

Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. The RNA-binding protein Hu antigen R (HuR) is upregulated in breast cancer, and elevated cytoplasmic HuR correlates with high-grade tumors and poor clinical outcome of breast cancer. HuR promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors, and cytokines that support major tumor hallmarks including invasion and metastasis. Here, we report a HuR inhibitor KH-3, which potently suppresses breast cancer cell growth and invasion. Furthermore, KH-3 inhibits breast cancer experimental lung metastasis, improves mouse survival, and reduces orthotopic tumor growth. Mechanistically, we identify FOXQ1 as a direct target of HuR. KH-3 disrupts HuR-FOXQ1 mRNA interaction, leading to inhibition of breast cancer invasion. Our study suggests that inhibiting HuR is a promising therapeutic strategy for lethal metastatic breast cancer.

DOI: https://doi.org/10.1038/s42003-020-0933-1
Cancer Res. 2020 Apr 20. pii: canres.3326.2019. [Epub ahead of print]

The EZH2-PHACTR2-AS1-ribosome axis induces genomic instability and promotes growth and metastasis in breast cancer.

Wenhui Chu, Xi Zhang, Lihua Qi, Yenan Fu, Peng Wang, Wei Zhao, Juan Du, Jing Zhang, Jun Zhan, Yunling Wang, Wei-Guo Zhu, Yu Yu, Hongquan Zhang.

Aberrant activation of histone methyltransferase EZH2 and ribosome synthesis strongly associate with cancer development and progression. We previously found that EZH2 regulates RNA polymerase III-transcribed 5S ribosomal RNA gene transcription. However, whether EZH2 regulates ribosome synthesis is still unknown. Here we report that EZH2 promotes ribosome synthesis by targeting and silencing a long non-coding RNA PHACTR2-AS1 (PAS1). PHACTR2-AS1 directly bound ribosome DNA genes and recruited histone methyltransferase SUV39H1, which in turn triggered H3K9 methylation of these genes. Depletion of PHACTR2-AS1 resulted in hyperactivation of ribosome synthesis and instability of ribosomal DNA, which promoted cancer cell proliferation and metastasis. Administration of PHACTR2-AS1-30nt-RNA, which binds to SUV39H1, effectively inhibited breast cancer growth and lung metastasis in mice. PHACTR2-AS1 was downregulated in breast cancer patients, where lower PHACTR2-AS1 expression promoted breast cancer development and correlated with poor patient outcome. Taken together, we demonstrate that PHACTR2-AS1 maintains a H3K9 methylation-marked silent state of ribosomal DNA genes, comprising a regulatory axis that controls breast cancer growth and metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3326
Nature. 2020 Apr 22.

A catalogue of cancer-driving mutations in healthy tissue.

Victoria L Bae-Jump, Douglas A Levine.



Keywords:  Cancer; Genomics; Medical research

DOI:  https://doi.org/10.1038/d41586-020-01081-6
Nat Cell Biol. 2020 Apr 20.

Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells.

John M Perry, Fang Tao, Anuradha Roy, Tara Lin, Xi C He, Shiyuan Chen, Xiuling Lu, Jacqelyn Nemechek, Linhao Ruan, Xiazhen Yu, Debra Dukes, Andrea Moran, Jennifer Pace, Kealan Schroeder, Meng Zhao, Aparna Venkatraman, Pengxu Qian, Zhenrui Li, Mark Hembree, Ariel Paulson, Zhiquan He, Dong Xu, Thanh-Huyen Tran, Prashant Deshmukh, Chi Thanh Nguyen, Rajeswari M Kasi, Robin Ryan, Melinda Broward, Sheng Ding, Erin Guest, Keith August, Alan S Gamis, Andrew Godwin, G Sitta Sittampalam, Scott J Weir, Linheng Li.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-β-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.

DOI: https://doi.org/10.1038/s41556-020-0507-y
Nat Commun. 2020 Apr 23. 11(1): 1961

LGR5 marks targetable tumor-initiating cells in mouse liver cancer.

Wanlu Cao, Meng Li, Jiaye Liu, Shaoshi Zhang, Lisanne Noordam, Monique M A Verstegen, Ling Wang, Buyun Ma, Shan Li, Wenshi Wang, Michiel Bolkestein, Michael Doukas, Kan Chen, Zhongren Ma, Marco Bruno, Dave Sprengers, Jaap Kwekkeboom, Luc J W van der Laan, Ron Smits, Maikel P Peppelenbosch, Qiuwei Pan.

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma. Isolated LGR5 expressing cells from mouse liver tumors are superior in initiating organoids and forming tumors upon engraftment, featuring candidate TICs. These cells are resistant to conventional treatment including sorafenib and 5-FU. Importantly, LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth. The combination of LGR5 ablation with 5-FU, but not sorafenib, further augments the therapeutic efficacy in vivo. Thus, we have identified the LGR5+ compartment as an important TIC population, representing a viable therapeutic target for combating liver cancer.

DOI: https://doi.org/10.1038/s41467-020-15846-0
Clin Cancer Res. 2020 Apr 22. pii: clincanres.3926.2019. [Epub ahead of print]

Longitudinal monitoring of ctDNA in patients with melanoma and brain metastases treated with immune checkpoint inhibitors.

Jenny H Lee, Alexander M Menzies, Matteo S Carlino, Ashleigh C McEvoy, Shahneen Sandhu, Alison M Weppler, Russell J Diefenbach, Sarah-Jane Dawson, Richard F Kefford, Michael J Millward, Zeyad Al-Ogaili, Thien Tra, Elin S Gray, Stephen Q Wong, Richard A Scolyer, Georgina V Long, Helen Rizos.

PURPOSE: Brain involvement occurs in majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation.
EXPERIMENTAL DESIGN: This study examined circulating BRAF, NRAS and c-KIT mutations in melanoma patients with active brain metastases receiving PD-1 inhibitor-based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analysed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/ml plasma).
RESULTS: Of a total of 72 patients; 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume (p < 0.01). Undetectable ctDNA on-therapy was associated with extracranial response (p < 0.01) but not intracranial response. The median overall survival in patients with undetectable (n = 34) versus detectable (n = 38) ctDNA at baseline was 39.2 versus 10.6 months (HR 0.51 [95% CI 0.28 - 0.94], p = 0.03) and on-therapy was 39.2 versus 9.2 months (HR 0.32 [95% CI 0.16 - 0.63], p < 0.01).
CONCLUSIONS: ctDNA remains a strong prognostic biomarker in melanoma patients with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-3926
Clin Cancer Res. 2020 Apr 24. pii: clincanres.1321.2020. [Epub ahead of print]

Dendritic cells, the T cell-inflamed tumor microenvironment and immunotherapy treatment response.

Christopher S Garris, Jason J Luke.

The development of the most successful cancer immunotherapies in solid tumors, immune-checkpoint blockade, has focused on factors regulating T cell activation. Until recently, the field has maintained a predominately T-cell centric view of immunotherapy, leaving aside the impact of innate immunity and especially myeloid cells. Dendritic cells (DC) are dominant partners of T cells, necessary for initiation of adaptive immune responses. Emerging evidence supports a broader role for DCs in tumors including the maintenance and support of effector functions during T cell responses. This relationship is evidenced by the association of activated DCs with immune-checkpoint blockade responses and transcriptional analysis of responding tumors demonstrating the presence of type I interferon transcripts and DC relevant chemokines. T cell-inflamed tumors preferentially respond to immunotherapies compared to non-T cell inflamed tumors and this model suggests a potentially modifiable spectrum of tumor microenvironmental immunity. While host and commensal factors may limit the T cell-inflamed phenotype, tumor cell intrinsic factors are gaining prominence as therapeutic targets. For example, tumor WNT/ᵷ1;-catenin signaling inhibits production of chemokine gradients and blocking DC recruitment to tumors. Conversely, mechanisms of innate immune nucleic acid sensing, normally operative during pathogen response, may enhance DC accumulation and make tumors more susceptible to cancer immunotherapy. Elucidating mechanisms whereby DCs infiltrate and become activated within tumors may provide new opportunities for therapeutic intervention. Conceptually, this would facilitate conversion of non-T cell-inflamed to T cell-inflamed states or overcome secondary resistance mechanisms in T cell-inflamed tumors, expanding the proportion of patients who benefit from cancer immunotherapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-1321
EMBO Mol Med. 2020 Apr 24. e11498

HER3 targeting with an antibody-drug conjugate bypasses resistance to anti-HER2 therapies.

Lucía Gandullo-Sánchez, Emily Capone, Alberto Ocaña, Stefano Iacobelli, Gianluca Sala, Atanasio Pandiella.

  Despite impressive clinical benefit obtained with anti-HER2-targeted therapies, in advances stages, especially in the metastatic setting, HER2-positive tumors remain incurable. Therefore, it is important to develop novel strategies to fight these tumors, especially when they become resistant to available therapies. We show here that the anti-HER3 antibody-drug conjugate EV20/MMAF exerted potent anti-tumoral properties against several models of primary resistance and secondary resistance to common anti-HER2 available therapies, including trastuzumab, lapatinib, neratinib, and trastuzumab-emtansine. HER3 was expressed in these HER2+ breast cancer cells and knockdown experiments demonstrated that HER3 expression was required for the action of EV20/MMAF. In mice injected with trastuzumab-resistant HER2+ cells, a single dose of EV20/MMAF caused complete and long-lasting tumor regression. Mechanistically, EV20/MMAF bound to cell surface HER3 and became internalized to the lysosomes. Treatment with EV20/MMAF caused cell cycle arrest in mitosis and promoted cell death through mitotic catastrophe. These findings encourage the clinical testing of EV20/MMAF for several indications in the HER2+ cancer clinic, including situations in which HER2+ tumors become refractory to approved anti-HER2 therapies.

Keywords:  HER2; HER3; breast cancer; drug resistance

DOI:  https://doi.org/10.15252/emmm.201911498
Nat Commun. 2020 Apr 20. 11(1): 1897

Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition.

Jenny H Lee, Elena Shklovskaya, Su Yin Lim, Matteo S Carlino, Alexander M Menzies, Ashleigh Stewart, Bernadette Pedersen, Malama Irvine, Sara Alavi, Jean Y H Yang, Dario Strbenac, Robyn P M Saw, John F Thompson, James S Wilmott, Richard A Scolyer, Georgina V Long, Richard F Kefford, Helen Rizos.

Transcriptomic signatures designed to predict melanoma patient responses to PD-1 blockade have been reported but rarely validated. We now show that intra-patient heterogeneity of tumor responses to PD-1 inhibition limit the predictive performance of these signatures. We reasoned that resistance mechanisms will reflect the tumor microenvironment, and thus we examined PD-1 inhibitor resistance relative to T-cell activity in 94 melanoma tumors collected at baseline and at time of PD-1 inhibitor progression. Tumors were analyzed using RNA sequencing and flow cytometry, and validated functionally. These analyses confirm that major histocompatibility complex (MHC) class I downregulation is a hallmark of resistance to PD-1 inhibitors and is associated with the MITFlow/AXLhigh de-differentiated phenotype and cancer-associated fibroblast signatures. We demonstrate that TGFß drives the treatment resistant phenotype (MITFlow/AXLhigh) and contributes to MHC class I downregulation in melanoma. Combinations of anti-PD-1 with drugs that target the TGFß signaling pathway and/or which reverse melanoma de-differentiation may be effective future therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-020-15726-7
Theranostics. 2020 ;10(11): 5107-5119

Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation.

Peng Chen, Xuejie Li, Ruonan Zhang, Shuiping Liu, Yu Xiang, Mingming Zhang, Xiaying Chen, Ting Pan, Lili Yan, Jiao Feng, Ting Duan, Da Wang, Bi Chen, Ting Jin, Wengang Wang, Liuxi Chen, Xingxing Huang, Wenzheng Zhang, Yitian Sun, Guohua Li, Lingpan Kong, Xiaohui Chen, Yongqiang Li, Zuyi Yang, Qin Zhang, Lvjia Zhuo, Xinbing Sui, Tian Xie.

  Background and Purpose: RAS mutations limit the effectiveness of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in combination with chemotherapy for metastatic colorectal cancer (mCRC) patients. Therefore, new cell death forms have focused on identifying indirect targets to inhibit Ras-induced oncogenesis. Recently, emerging evidence has shown the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Methods: KRAS mutant CRC cell HCT116 and Lovo were treated with cetuximab and β-elemene, a bioactive compound isolated from Chinese herb Curcumae Rhizoma. Ferroptosis and epithelial-mesenchymal transformation (EMT) were detected in vitro and in vivo. Orthotopic CRC animal model were established and the tumor growth was monitored by IVIS bioluminescence imaging. Tumor tissues were collected to determine ferroptosis effect and the expression of EMT markers after the treatment. Results: CCK-8 assay showed that synergetic effect was obtained when 125 µg/ml β-elemene was combined with 25 µg/ml cetuximab in KRAS mutant CRC cells. AV/PI staining suggested a non-apoptotic mode of cell death after the treatment with β-elemene and cetuximab. In vitro, β-elemene in combination with cetuximab was shown to induce iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of HO-1 and transferrin, and downregulation of negative regulatory proteins for ferroptosis (GPX4, SLC7A11, FTH1, glutaminase, and SLC40A1) in KRAS mutant CRC cells. Meanwhile, combinative treatment of β-elemene and cetuximab inhibited cell migration and decreased the expression of mesenchymal markers (Vimentin, N-cadherin, Slug, Snail and MMP-9), but promoted the expression of epithelial marker E-cadherin. Moreover, ferroptosis inhibitors but not other cell death suppressors abrogated the effect of β-elemene in combination with cetuximab on KRAS mutant CRC cells. In vivo, co-treatment with β-elemene and cetuximab inhibited KRAS mutant tumor growth and lymph nodes metastases. Conclusions: Our data for the first time suggest that the natural product β-elemene is a new ferroptosis inducer and combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant CRC cells by inducing ferroptosis and inhibiting EMT, which will hopefully provide a prospective strategy for CRC patients with RAS mutations.

Keywords:  KRAS mutation; colorectal cancer; epithelial-mesenchymal transformation; ferroptosis; β-elemene

DOI:  https://doi.org/10.7150/thno.44705
Clin Cancer Res. 2020 Apr 20. pii: clincanres.3953.2019. [Epub ahead of print]

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination With Fulvestrant in Patients With AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.

Lillian M Smyth, Kenji Tamura, Mafalda Oliveira, Eva M Ciruelos, Ingrid A Mayer, Marie-Paule Sablin, Laura Biganzoli, Helen J Ambrose, Jack Ashton, Alan Barnicle, Des D Cashell, Claire Corcoran, Elza C de Bruin, Andrew Foxley, Joana Hauser, Justin P O Lindemann, Rhiannon Maudsley, Robert McEwen, Michele Moschetta, Martin Pass, Vicky Rowlands, Gaia Schiavon, Udai Banerji, Maurizio Scaltriti, Barry S Taylor, Sarat Chandarlapaty, Jose Baselga, David M Hyman.

PURPOSE: The activating mutation AKT1 E17K occurs in ~7% of ER+ metastatic breast cancer (MBC). We report, from a multipart, first-in-human, Phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of AKT1 E17K-mutant ER+ MBC patients.
PATIENTS AND METHODS: Patients with an AKT1 E17K mutation, detected by local (NGS) or central (plasma-based BEAMing) testing, received capivasertib 480 mg bid, 4 days on, 3 days off, weekly or 400 mg bid combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS) and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.
RESULTS: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although this latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), ddPCR (80%, 33/41) and NGS (76%, 31/41). A 50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy (most frequent grade ≥3 adverse events: rash [9% vs 20%], hyperglycemia [5% vs 30%], diarrhea [5% vs 10%]).
CONCLUSIONS: Capivasertib demonstrated clinically meaningful activity in heavily pretreated AKT1 E17K-mutant ER+ MBC patients, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-3953
J Clin Invest. 2020 Apr 21. pii: 130379. [Epub ahead of print]

HuR/ELAVL1 drives malignant peripheral nerve sheath tumour growth and metastasis.

Marta Palomo-Irigoyen, Encarnación Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia Telletxea, Daniela Medrano, David Fernández-Ramos, Juan-Jose Lozano, Satoshi Okawa, José Luis Lavín, Natalia Martin-Martin, James D Sutherland, Virginia Gutiérrez-de Juan, Monika Gonzalez-Lopez, Nuria Macias-Camara, David Mosén-Ansorena, Liyam Laraba, C Oliver Hanemann, Emanuela Ercolano, David B Parkinson, Christopher W Schultz, Marcos J Araúzo-Bravo, Alex M Ascensión, Daniela Gerovska, Haizea Iribar, Ander Izeta, Peter Pytel, Philipp Krastel, Alessandro Provenzani, Pierfausto Seneci, Ruben D Carrasco, Antonio Del Sol, Maria L Martinez Chantar, Rosa Barrio, Eduard Serra, Conxi Lázaro, Adrienne M Flanagan, Myriam Gorospe, Nancy Ratner, Arkaitz Carracedo, Ana María Aransay, Marta Varela-Rey, Ashwin Woodhoo.

  Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumours (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumour growth, and strongly supressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/beta-Catenin, YAP/TAZ, Rb-E2F and BET proteins, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.

Keywords:  Cancer; Cell Biology; Epigenetics; Oncogenes; Oncology

DOI:  https://doi.org/10.1172/JCI130379
EMBO Rep. 2020 Apr 23. e50468

Stromal deactivation by CSF1: a new feature of the aggressive pancreatic cancer microenvironment.

Renzo E Vera, Martin E Fernandez-Zapico.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with one of the poorest prognosis among all malignancies. The initiation and evolution of this kind of tumor depends on a complex interaction between cancer cells and the tumor microenvironment (TME). In an elegant study, Steins et al [1] used a combination of relevant disease models to show that mesenchymal subtype of PDAC shows a distinct deactivation of stellate cells in a CSF1-dependent fashion. This study shedding light on a new role for the stroma driving an aggressive PDAC subtypes shifts the current paradigm for the requirement of an activated TME to regulate PDAC growth and maintenance.

DOI: https://doi.org/10.15252/embr.202050468