CMMC: Hillmer, Axel - assoc. RG 09

Abstract

Esophageal adenocarcinoma (EAC) incidence rose dramatically over the last decades. Since genomic analyses did not reveal common targets for therapies, treatment options are limited and prognosis is poor. EAC patients show large differences in response to neoadjuvant treatment but no biomarkers are known that predict initial and long term response to therapy.

It has been demonstrated for some solid tumors that cancer associated fibroblasts (CAFs) play an important role in tumor biology and for metastases. To investigate whether functional changes in CAFs are responsible for differences in treatment response and early metastases, cell type-specific transcriptome analyses are needed. It is now possible to perform single cell transcriptomics but this approach is still not scalable to investigate enough samples for clinical association. We have developed a protocol that combines fluorescence activated cell sorting with RNA-seq, allowing to analyse the transcriptomes of leukocytes, epithelial cells and fibroblasts separately.

We will apply this concept to treatment naïve EAC biopsies and normal tissues and will systematically identify cell-type specific alterations that correspond to treatment response and relapse. We will validate our findings using a large collection of EAC tissues for targeted assays and by experiments in tissue culture. Overall, we will be able to identify functional changes in CAFs and other tumor components that will help to explain the clinical course of an EAC patient and that provide new opportunities for intervention.

Clinical and Medical Relevance

A better understanding of the tumor microenvironment with its different cell types is needed to clarify their roles for treatment response and disease progression of EAC.

We will define the transcriptomic profiles of leukocytes, fibroblasts and epithelial cells of EAC and normal tissue and will identify critical pathways in CAFs that correlate with treatment response and metastases. We will use this information to derive opportunities for new treatment concepts.

Project Related Publications

Chen J, Zhang T, Yang H, Teo ASM, Amer LB, Sherbaf FG, Tan CQ, Alvarez JJS, Lu B, Lim JQ, Takano A, Nahar R, Lee YY, Phua CZJ, Chua KP, Suteja L, Chen PJ, Chang MM, Koh TPT, Ong BH, Anantham D, Hsu AAL, Gogna A, Too CW, Aung ZW, Lee YF, Wang L, Lim TKH, Wilm A, Choi DPS, Ng PY, Toh CK, Lim WT, Ma S, Lim B, Liu J, Tam WL, Skanderup AMJ, Yeong JPS, Tan EH, Creasy C, Tan DSW*, Hillmer AM*, Zhai W*. (2020) Genomic landscape and ethnic specificity of lung adenocarcinoma in Asia. Nat Genet (accepted)
Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY, Chong PKW, Teo CC, Ang HY, Peh KLE, Yuan J, Ma S, Choo LSK, Basri N, Jiang X, Yu Q, Hillmer AM, Lim WT, Lim TKH, Takano A, Tan EH, Tan DSW, Ho YS, Lim B, Tam WL (2019) Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 25:825-837
Kong SL, Li H, Tai JA, Courtois ET, Poh HM, Lau DP, Haw YX, Iyer NG, Tan DSW, Prabhakar S, Ruff D, Hillmer AM (2019) Concurrent Single-Cell RNA and Targeted DNA Sequencing on an Automated Platform for Comeasurement of Genomic and Transcriptomic Signatures. Clin Chem 65:272-281
Simoni Y, Becht E, Fehlings M, Loh CY, Koo S-L, Teng KWW, Yeong JPS, Nahar R, Zhang T, Kared H, Duan K, Ang N, Podinger M, Lee YY, Larbi A, Khng AJ, Tan E, Fu D, Mathew R, Teo M, Lim WT, Toh CK, Ong BH, Koh T, Hillmer AM, Takano A, Lim TKH, Tan EH, Weiwei Z, Tan ESW, Tan IB, Newell EW (2018) Bystander CD8+ T cells are abundant in human tumour infiltrates and lack expression of CD39. Nature 557:575-579
Nahar R, Zhai W, Zhang T, Takano A, Khng AJ, Lee YY, Liu X, Lim CH, Koh TPT, Aung Z, Lim TKH, Veeravalli L, Yuan J, Teo ASM, Chan CX, Poh HM, Chua IML, Liew AA, Lau DPX, Kwang XL, Toh CK, Lim WT, Lim B, Tam WL, Tan E-H, Hillmer AM#, Tan DSW# (2018) Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat Commun 9:216 (#corresponding author)
Li H, Courtois ET, Sengupta D, Tan Y, Chen KH, Goh JJL, Kong SL, Chua C, Hon LK, Tan WS, Wong M, Choi PJ, Wee LJK, Hillmer AM, Tan IB, Robson P, Prabhakar S (2017) Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat Genet 49:708-718
Cima I, Kong SL, Sengupta D, Tan IB, Phyo WM, Lee D, Hu M, Iliescu C, Alexander I, Goh WL, Rahmani M, Suhaimi N-AM, Vo JH, Tai JA, Tan JH, Chua C, Ten R, Lim WJ, Chew MH, Hauser CAE, van Dam RM, Lim W-Y, Prabhakar S, Lim B, Koh PK, Robson P, Ying JY, Hillmer AM, Tan MH (2016) Tumor-derived circulating endothelial cell clusters in colorectal cancer. Sci Transl Med 8:345ra89
Yao F*, Kausalya JP*, Sia YY, Teo ASM, Lee WH, Ong AGM, Zhang Z, Tan JHJ, Li G, Bertrand D, Liu X, Poh HM, Guan P, Zhu F, Pathiraja TN, Ariyaratne PN, Rao J, Woo XY, Cai S, Mulawadi FH, Poh WT, Veeravalli L, Chan CS, Lim SS, Leong ST, Neo SC, Choi PSD, Chew EGY, Nagarajan N, Jacques P-E, So JBY, Ruan X, Yeoh KG, Tan P, Sung W-K, Hunziker W#, Ruan Y#, Hillmer AM# (2015) Recurrent fusion genes in gastric cancer: CLDN18-ARHGAP26 induces loss of epithelial integrity. Cell Rep 12:272-85 (*contributed equally, #corresponding author)

Publications 2021

Kong SL, Liu X, Tan SJ, Tai JA, Phua LY, Poh HM, Yeo T, Chua YW, Haw YX, Ling WH, Ng RCH, Tan TJ, Loh KWJ, Tan DS, Ng QS, Ang MK, Toh CK, Lee YF, Lim CT, Lim TKH, Hillmer AM, Yap YS, and Lim WT (2021). Complementary Sequential Circulating Tumor Cell (CTC) and Cell-Free Tumor DNA (ctDNA) Profiling Reveals Metastatic Heterogeneity and Genomic Changes in Lung Cancer and Breast Cancer. Front Oncol11, 698551. doi:10.3389/fonc.2021.698551.

Li J, Wu X, Schiffmann L, MacVicar T, Zhou C, Wang Z, Li D, Camacho OV, Heuchel R, Odenthal M, Hillmer A, Quaas A, Zhao Y, Bruns CJ, and Popp FC (2021). IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth. Cancers (Basel)13. doi:10.3390/cancers13215338.

Tan JHJ, Kong SL, Tai JA, Poh HM, Yao F, Sia YY, Lim EKH, Takano AM, Tan DS, Javed A, and Hillmer AM (2021). Experimental and bioinformatics considerations in cancer application of single cell genomics. Comput Struct Biotechnol J19, 343-354. doi:10.1016/j.csbj.2020.12.021.

Hoppe S, Jonas C, Wenzel MC, Velazquez Camacho O, Arolt C, Zhao Y, Buttner R, Quaas A, Plum PS, and Hillmer AM (2021). Genomic and Transcriptomic Characteristics of Esophageal Adenocarcinoma. Cancers (Basel)13. doi:10.3390/cancers13174300.

Publications 2020

Kramer M, Plum PS, Velazquez Camacho O, Folz-Donahue K, Thelen M, Garcia-Marquez I, Wolwer C, Busker S, Wittig J, Franitza M, Altmuller J, Loser H, Schlosser H, Buttner R, Schroder W, Bruns CJ, Alakus H, Quaas A, Chon SH, and Hillmer AM (2020). Cell type-specific transcriptomics of esophageal adenocarcinoma as a scalable alternative for single cell transcriptomics. Mol Oncol 14, 1170-84.

Zhou C, Fan N, Liu F, Fang N, Plum PS, Thieme R, Gockel I, Gromnitza S, Hillmer AM, Chon SH, Schlosser HA, Bruns CJ, and Zhao Y (2020). Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer. Cells 9.

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Hillmer, Axel - assoc. RG 09

Dissecting the role of cancer associated fibroblasts of esophageal adenocarcinoma for response to radiochemotherapy

Abstract

Clinical and Medical Relevance

Project Related Publications

Publications 2021

Publications 2020

Prof. Dr. Axel Hillmer

Publications - Axel Hillmer

Figure 1