LRG1 is a novel HER3 ligand to promote growth in colorectal cancer

Therapy failure for patients with metastatic colorectal cancer (mCRC) remains an overarching challenge in the clinic. We find that liver endothelial cells secrete soluble factor(s) to promote mCRC growth in vitro and in vivo. We identify LRG1 in ECs secretome, which promotes growth in tumor cells through binding and activation of HER3. Pharmacological blocking of the LRG1/HER3 axis using LRG1 antibody 15C4 completely attenuated LRG1-induced HER3 activation and in vitro and in vivo growth of the tumor. Moreover, LRG1-/- mice with CRC allografts in the liver had 2 times longer overall survival than tumor-bearing LRG1+/+ mice. Lastly, unbiased -omics analysis and target-specific inhibitors identified eIF4-protein synthesis is significantly activated by the LRG1/HER3/RSK1/2 axis. This work reveals a paracrine mechanism of mCRC growth in liver microenvironment and highlighted the potential of blocking LRG1-HER3 and involved downstream pathways for treating patients with mCRC.

[1]  Rui Wang,et al.  Liver Endothelium Microenvironment Promotes HER3-mediated Cell Growth in Pancreatic ductal adenocarcinoma , 2022, bioRxiv.

[2]  L. Ellis,et al.  Liver Endothelium Promotes HER3-mediated Cell Survival in Colorectal Cancer with Wild-type and Mutant KRAS. , 2022, Molecular cancer research : MCR.

[3]  S. Moss,et al.  LRG1: an emerging player in disease pathogenesis , 2022, Journal of biomedical science.

[4]  S. Moss,et al.  LRG1 as a novel therapeutic target in eye disease , 2022, Eye.

[5]  E. Van Cutsem,et al.  First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Shubhada R. Kulkarni,et al.  Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis , 2021, Science Translational Medicine.

[7]  W. Wahli,et al.  LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling , 2021, Cancers.

[8]  Shubhada R. Kulkarni,et al.  A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie–Wnt signaling axis in the liver , 2021, Developmental cell.

[9]  P. Jänne,et al.  Thirty Years of HER3: From Basic Biology to Therapeutic Interventions , 2021, Clinical Cancer Research.

[10]  R. Francés,et al.  Role of liver sinusoidal endothelial cells in liver diseases , 2021, Nature Reviews Gastroenterology & Hepatology.

[11]  Jiang Ren,et al.  Targeting TGFβ signal transduction for cancer therapy , 2021, Signal Transduction and Targeted Therapy.

[12]  Emma Minnee,et al.  Translation initiation and its relevance in colorectal cancer , 2020, The FEBS journal.

[13]  Tianrui Xu,et al.  Eukaryotic translation initiation factors as promising targets in cancer therapy , 2020, Cell Communication and Signaling.

[14]  O. Sansom,et al.  LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency , 2020, bioRxiv.

[15]  J. Greenwood,et al.  A Humanized Antibody against LRG1 that Inhibits Angiogenesis and Reduces Retinal Vascular Leakage , 2020, bioRxiv.

[16]  U. Güller,et al.  Population-based SEER analysis of survival in colorectal cancer patients with or without resection of lung and liver metastases , 2020, BMC Cancer.

[17]  Jing-Yuan Fang,et al.  Comprehensive review of targeted therapy for colorectal cancer , 2020, Signal Transduction and Targeted Therapy.

[18]  Kaoru Tanaka,et al.  U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation. , 2019, The Journal of clinical investigation.

[19]  K. Andrabi,et al.  Eukaryotic initiation factor 4E (eIF4E): A recap of the cap‐binding protein , 2019, Journal of cellular biochemistry.

[20]  Steven J. M. Jones,et al.  NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma , 2019, Clinical Cancer Research.

[21]  Edward S. Kim,et al.  Detection of NRG1 Gene Fusions in Solid Tumors , 2019, Clinical Cancer Research.

[22]  L. Sequist,et al.  Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer. , 2019, The oncologist.

[23]  C. Jin,et al.  LRG-1 promotes pancreatic cancer growth and metastasis via modulation of the EGFR/p38 signaling , 2019, Journal of experimental & clinical cancer research : CR.

[24]  David Bonekamp,et al.  NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer. , 2018, Cancer discovery.

[25]  L. Ellis,et al.  Endothelial Cells Promote Colorectal Cancer Cell Survival by Activating the HER3-AKT Pathway in a Paracrine Fashion , 2018, Molecular Cancer Research.

[26]  Takami Sato,et al.  Immunological aspect of the liver and metastatic uveal melanoma , 2017 .

[27]  J. Desai,et al.  Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. , 2017, The Lancet. Oncology.

[28]  T. Ohkawara,et al.  Leucine-rich alpha 2 glycoprotein promotes Th17 differentiation and collagen-induced arthritis in mice through enhancement of TGF-β-Smad2 signaling in naïve helper T cells , 2017, Arthritis Research & Therapy.

[29]  L. Ellis,et al.  Endothelial cells activate the cancer stem cell‐associated NANOGP8 pathway in colorectal cancer cells in a paracrine fashion , 2017, Molecular oncology.

[30]  Ying Zhou,et al.  LRG1 promotes proliferation and inhibits apoptosis in colorectal cancer cells via RUNX1 activation , 2017, PloS one.

[31]  S. Steinberg,et al.  Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750—an antisense oligonucleotide against eIF4E—in combination with irinotecan in solid tumors and irinotecan‐refractory colorectal cancer , 2016, International journal of cancer.

[32]  K. Kinzler,et al.  Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer , 2016, Nature Communications.

[33]  R. Cuesta,et al.  RSK-mediated down-regulation of PDCD4 is required for proliferation, survival, and migration in a model of triple-negative breast cancer , 2016, Oncotarget.

[34]  Y. Yarden,et al.  Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3 , 2016, Human Vaccines & Immunotherapeutics.

[35]  Jingyuan Fang,et al.  LRG1 modulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via HIF-1α activation , 2016, Journal of experimental & clinical cancer research : CR.

[36]  L. Ellis,et al.  A Disintegrin and Metalloproteinase Domain 17 Regulates Colorectal Cancer Stem Cells and Chemosensitivity Via Notch1 Signaling , 2016, Stem cells translational medicine.

[37]  T. Ohkawara,et al.  Leucine-rich α-2-glycoprotein promotes TGFβ1-mediated growth suppression in the Lewis lung carcinoma cell lines , 2015, Oncotarget.

[38]  I. Nagtegaal,et al.  Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies , 2014, Clinical Cancer Research.

[39]  J. Greenwood,et al.  LRG1 promotes angiogenesis by modulating endothelial TGF-beta signalling (vol 499, pg 306, 2013) , 2013 .

[40]  S. Markowitz,et al.  Gain of interaction with IRS1 by p110α-helical domain mutants is crucial for their oncogenic functions. , 2013, Cancer cell.

[41]  L. Ellis,et al.  Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. , 2013, Cancer cell.

[42]  S. Hanash,et al.  Increased Plasma Levels of the APC-Interacting Protein MAPRE1, LRG1, and IGFBP2 Preceding a Diagnosis of Colorectal Cancer in Women , 2012, Cancer Prevention Research.

[43]  Philippe P Roux,et al.  Regulation and function of the RSK family of protein kinases. , 2012, The Biochemical journal.

[44]  H. Manji,et al.  Evidence for Involvement of ERK, PI3K, and RSK in Induction of Bcl-2 by Valproate , 2009, Journal of Molecular Neuroscience.

[45]  M. Ligtenberg,et al.  Deficient mismatch repair system in patients with sporadic advanced colorectal cancer , 2009, British Journal of Cancer.

[46]  Qiang Wang,et al.  ErbB receptors: from oncogenes to targeted cancer therapies. , 2007, The Journal of clinical investigation.

[47]  Brian Raught,et al.  The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity , 2006, The EMBO journal.

[48]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Walter Gilbert,et al.  Ligands for ErbB-family receptors encoded by a neuregulin-like gene , 1997, Nature.

[50]  K. Kinzler,et al.  Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. , 1995, Science.