CHEW Guo-Liang

Special Fellow, Cancer Science Institute of Singapore, NUS

guoliang[at]nus.edu.sg


To persist and spread in the human body, cancers have to hide from the immune system. How do cancers do this? We have found that cancers sometimes reuse the same programs that the developing embryo uses to suppress immune attack from the mother. By understanding the molecular details of how cancers reactivate these programs to suppress immunity, we aim to uncover new therapeutic approaches for treating cancer.

Research

Our research group seeks to understand how reactivated developmental genes help cancers evade the immune system. Such genes may reprise endogenous immunosuppressive roles to promote cancer progression: determining their molecular mechanisms of action in cancer and development will yield insight into how cancers block immune surveillance, and how we might design therapeutic approaches around them.

Tumors frequently reactivate genes that are not otherwise expressed in normal adult tissue, including genes with prior roles in development (Fig. 1). Their expression in cancer is typically rationalized as driving cancer-relevant developmental processes such as pluripotency, proliferation and angiogenesis.

However, in recent work, we have uncovered an unexpected immunosuppressive role for such a gene: the reactivation of DUX4, an embryonic transcription factor whose misexpression also causes facioscapulohumeral muscular dystrophy (a common muscle dystrophy), suppresses antigen presentation across many cancer types, and is associated with reduced response to immune checkpoint inhibitors (Chew*, Campbell* et al. Dev Cell 2019) (Fig. 2).

In parallel, we have found several other developmental genes that are also reactivated across various cancers. Preliminary analyses have found many of these genes to be similarly associated with immune suppression in cancer, albeit in different aspects of immunity, and in different sets of cancers.

These findings suggest a generally unexplored role of many developmental genes in suppressing immunity, both in their endogenous developmental context, as well as in cancer. Understanding the mechanisms for how such reactivated developmental genes suppress the immune system will inform our approaches to the treatment of immune-evading cancers.

 

Our aims are to determine the molecular and gene-regulatory mechanisms underlying:

  1. how reactivated developmental genes in cancer promotes immune suppression,
  2. how these developmental genes become reactivated in cancer, and
  3. how this immune suppression might be reversed to restore immune activity against cancers.

 

To do so, we take an integrative data science and experimental approach, collaborating closely with clinician scientists to iterate between mechanistically-informed analyses of patient data, and high-throughput experiments in relevant cellular and animal models.

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Selected Publications

1. Inoue D*, Chew GL*, Liu B, Michel BC, Pangallo J, D’Avino AR, Hitchman T, North KD, Lee SCW, Bitner L, Block A, Moore AR, Yoshimi A, Escobar-Hoyos L, Cho H, Penson S, Lu SX, Taylor J, Chen Y, Kadoch C, Abdel-Wahab O, Bradley RK. Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature. 2019 Oct; 574(7778):432-436. *Co-first author

2. Chew GL*, Campbell AE*, De Neef EJ, Sutliff NA, Shadle SC, Tapscott SJ, Bradley RK. DUX4 suppresses MHC Class I expression to promote cancer escape from immune surveillance and resistance to checkpoint blockade therapy. Dev Cell.2019 Sep 9;50(5):658-671. *Co-first author

3. Rabani M, Pieper L, Chew GL, Schier AF. Massively parallel reporter assay of 3’UTR sequences identifies in vivo rules for mRNA degradation. Mol Cell. 2017 Dec 21;68(6):1083-1094.e5.

4. Hassan M, Vasquez JJ, Chew GL, Meissner M, Siegel N. Comparative ribosome profiling uncovers a dominant role for translational control in Toxoplasma gondii. BMC Genomics. 2017 Dec 11;18(1):961.

5. Li JJ, Chew GL, Biggin MD. Quantitating translational control: mRNA abundance-dependent and independent contributions and the mRNA sequences that specify them. Nucleic Acids Res. 2017 Nov 16;45(20):11821-11836.

6. Chew GL*, Pauli A, Schier AF. Conservation of uORF repressiveness and sequence features in mouse, human and zebrafish. Nat Commun. 2016 May 24;7:11663. *Corresponding author

7. Pauli A, Norris ML, Valen E, Chew GL, Gagnon JA, Zimmerman S, Mitchell A, Ma J, Dubrulle J, Reyon D, Tsai SQ, Joung JK, Saghatelian A, Schier AF. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science. 2014 Feb 14;343(6172):1248636

8. Chew GL, Pauli A, Rinn JL, Regev A, Schier AF, Valen E. Ribosome profiling reveals resemblance between long non-coding RNAs and 5′ leaders of coding RNAs. Development. 2013 Jul;140(13):2828-34

9. Antos JM, Chew GL, Guimaraes CP, Yoder NC, Grotenbreg GM, Popp MW, Ploegh HL. Site-specific N- and C-terminal labeling of a single polypeptide using sortases of different specificity. J Am Chem Soc. 2009 Aug 12;131(31):10800-1

10. Antos JM, Popp MW, Ernst R, Chew GL, Spooner E, Ploegh HL. A straight path to circular proteins.  J Biol Chem. 2009 Jun 5;284(23):16028-36

Honors & Awards

2015 – 2017 Mahan Fellow (Fred Hutchinson Cancer Research Center)
2012 – 2015 International Student Research Fellowship (Howard Hughes Medical Institute)
2011 Mazur Fellow (Harvard University)
2010 Peirce Fellow (Harvard University)