Senthil Muthuswamy

Senthil Muthuswamy, PhD

Investigating the biology of normal and cancer epithelial cells within an organ-like microenvironment

Our overall goal is to investigate the biology of normal and cancer epithelial cells within a tissue-like context. To do so, we have developed and use three-dimensional (3D) organoid culture systems to grow breast and pancreatic epithelial ducts from immortalized, primary or pluripotent cells. Cells in 3D cultures integrate signals from growth factors, cell-cell and cell-matrix interactions to generate structures that look and function like mini-organs. Their use helps us bridge the gap between in vitro and in vivo systems to understand tissue morphogenesis and to identify new targets, biomarkers and develop therapies to conquer cancer.

Using these organoid cultures we have discovered how cell polarity proteins such as SCRIBBLE, PARD3 and PARD6 cooperate with oncogenes (ERBB2 and MYC) during cancer initiation and cancer cell metastasis. We continue to use these 3D organoid cultures to identify better markers for detecting changes in cell polarity and to investigate how cell polarity proteins regulate signaling pathways involved in cell death, cell junctions, differentiation and epithelial to mesenchymal transition during both cancer progression and response to therapeutic drugs.
These 3D organoid systems are also excellent platforms for understanding normal ductal morphogenesis of epithelial cells. By combining real-time imaging and 3D culture, we discovered that epithelial organoids rotate 360 degrees every four hours during morphogenesis to assemble their basement membrane matrix. Since invasive cancers in vivo are either devoid-of or have abnormal basement membranes, it is likely that the mechanophysical aspect of organoid morphogensis are novel regulators of invasive behavior. We continue to investigate the mechanics and dynamics of cell behavior during ductal morphogenesis to identify pathways that regulate basement membrane assembly, cell polarization, growth control and organ size control.

Finally, we translate the observations using 3D models to the in vivo context by developing and using inducible transgenic mice, differentiation-state lineage reporter mice and tumor xenograft models to understand how pathways regulated by cell polarity proteins affect normal cell differentiation and differentiation status of tumor cells during tumor initiation, progression and response to therapy. We use these models to identify ways to promote cancer cell differentiation, which could lead to identification of new therapeutic options to control cancer.
Nat Cell Biol. 2016 Oct 03;:
Zheng W, Umitsu M, Jagan I, Tran CW, Ishiyama N, BeGora M, Araki K, Ohashi PS, Ikura M, Muthuswamy SK
J Cell Sci. 2016 May 13;
Baker L, BeGora M, Au Yeung F, Feigin ME, Rosenberg AZ, Lowe SW, Kislinger T, Muthuswamy SK
Biophys J. 2016 Apr 26;110(8):1886-95
Milano DF, Ngai NA, Muthuswamy SK, Asthagiri AR
Nat Med. 2015 Oct 26;
Huang L, Holtzinger A, Jagan I, BeGora M, Lohse I, Ngai N, Nostro C, Wang R, Muthuswamy LB, Crawford HC, Arrowsmith C, Kalloger SE, Renouf DJ, Connor AA, Cleary S, Schaeffer DF, Roehrl M, Tsao MS, Gallinger S, Keller G, Muthuswamy SK
Nat Chem Biol. 2014 Jul;10(7):558-66
Krishnan N, Koveal D, Miller DH, Xue B, Akshinthala SD, Kragelj J, Jensen MR, Gauss CM, Page R, Blackledge M, Muthuswamy SK, Peti W, Tonks NK
Cancer Res. 2014 Jun 1;74(11):3180-94
Feigin ME, Akshinthala SD, Araki K, Rosenberg AZ, Muthuswamy LB, Martin B, Lehmann BD, Berman HK, Pietenpol JA, Cardiff RD, Muthuswamy SK
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):163-8
Wang H, Lacoche S, Huang L, Xue B, Muthuswamy SK
Mol Cell. 2012 Aug 10;47(3):469-83
Yang Z, Xue B, Umitsu M, Ikura M, Muthuswamy SK, Neel BG